bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–03–16
forty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Evidence-based risk stratification of myeloid neoplasms harboring TP53 mutations.
  2. Multihit TP53 Mutations in Myeloproliferative Neoplasms and Acute Myeloid Leukemia: Comparative Analysis of Survival and Risk Factors in 142 Informative Cases.
  3. Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia With Myelodysplasia-Related Genetic Features: Relevance of the Genetic Underlying Category. A Retrospective Analysis on Behalf of the Acute Leukemia Working Party of the EBMT.
  4. TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling.
  5. CCRL2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53.
  6. Factors associated with survival following allogeneic transplantation for myeloid neoplasms harboring TP53 mutations.
  7. Phosphoproteomics identifies determinants of PAK inhibitor sensitivity in leukaemia cells.
  8. Enforcement of stem-cell dormancy by nucleophosmin mutation is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis.
  9. Clonal Hematopoiesis Landscape in Frequent Blood Donors.
  10. Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system.
  11. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial.
  12. Real-World Outcomes of Relapsed/Refractory Core-Binding Factor Acute Myeloid Leukemia: A COMMAND Registry Study.
  13. Impact of hematopoietic cell transplantation and quizartinib in newly diagnosed patients with acute myeloid leukemia and FMS-like tyrosine kinase 3-internal tandem duplications in the QuANTUM-First trial.
  14. SOHO State of the Art Updates and Next Questions Acute Myeloid Leukemia: Current Status and Next Questions.
  15. Outcome of Patients with IDH-mutated AML following Allogeneic Stem Cell Transplantation - a Retrospective Analysis on behalf of the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy, DRST.
  16. Social Determinants of Health and Access to Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia.
  17. Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F.
  18. Allogeneic Stem Cell Transplant for Myelofibrosis and Myelodysplastic Syndromes: A Contemporary Review.
  19. TP53-Mutated Myeloid Neoplasms: 2024 Update on Diagnosis, Risk-Stratification, and Management.
  20. Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import.
  21. SMYD3 Activates Fatty Acid β-oxidation to Promote Self-Renewal of Leukemia Stem Cells.
  22. In the Right Place and the Right State: Spatial Crosstalk and Immune State Dictate Leukemia Response to Immunotherapy.
  23. Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes.
  24. Gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia: a regional analysis of COMMODORE in China, South-East Asia, and Russia.
  25. Periarteriolar niches become inflamed in aging bone marrow, remodeling the stromal microenvironment and depleting lymphoid progenitors.
  26. Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.
  27. Impact of treatment for adolescent and young adults with essential thrombocythemia and polycythemia vera.
  28. Succinate dehydrogenase activity supports de novo purine synthesis.
  29. Influence of Hypoxia on a Biomaterial Model of the Bone Marrow Perivascular Niche.
  30. Monitoring the KMT2A gene post-chemotherapy independently predicts the relapse and survival risk after allogeneic haematopoietic stem cell transplantation.
  31. Topics of Interest in Women With Myeloproliferative Neoplasms.
  32. Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives.
  33. Continuous map of early hematopoietic stem cell differentiation across human lifetime.
  34. RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and WNT pathway activation.
  35. Comparison of subcutaneous injection versus intravenous infusion of cytarabine for induction therapy in adult acute myeloid leukemia.
  36. Cell-free DNA for detection and monitoring of extramedullary AML relapse.
  37. Efficacy of first-line tagraxofusp in blastic plasmacytoid dendritic cell neoplasm with prior or concomitant hematologic malignancy: subgroup analysis of a pivotal trial.
  38. OTUB1 promotes the progression of acute myeloid leukemia by regulating glycolysis via deubiquitinating c-Myc.
  39. Impact of Donor Age and Donor Cytomegalovirus Serostatus on Outcomes After Related Donor Allogeneic Hematopoietic Stem Cell Transplantation.
  40. Mature Megakaryocytes Acquire Immune Characteristics in a Mouse Model of Aplastic Anemia.
  41. Classification of Myelodysplastic, Myeloproliferative, and Myelodysplastic/Myeloproliferative Neoplasms: The Past, Present, and Future.
  1. Blood Adv. 2025 Mar 14. pii: bloodadvances.2024015238. [Epub ahead of print]
    Evidence-based risk stratification of myeloid neoplasms harboring TP53 mutations.
    Mithun Vinod Shah, Kevin Hung, Anmol Baranwal, Monika M Kutyna, Aref Al-Kali, Carla Toop, Patricia T Greipp, Anna L Brown, Syed Naseem Shah, Shreyas Khanna, Dariusz Ladon, Vedavyas Gannamani, Dong Chen, Kebede Begna, Zoe Price, Danielle Rud, Mark R Litzow, William J Hogan, Peter G Bardy, Talha Badar, Sharad Kumar, David T Yeung, Mrinal M Patnaik, James M Foran, Rong He, Naseema Gangat, Hamish S Scott, Cecilia Arana-Yi, Hassan B Alkhateeb, Abhishek A Mangaonkar, Daniel Thomas, Christopher N Hahn, Attilio Orazi, Daniel A Arber, Chung Hoow Kok, Ayalew Tefferi, Devendra K Hiwase.
      This retrospective analysis aimed to provide evidence-based risk-stratification of TP53-mutated (TP53mut) myeloid neoplasms (MN). Of 580 MN harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.4%), 92 (15.9%), and 75 (12.9%) were classified as acute myeloid leukemia (AML), MDS with low blasts (MDS-LB), MDS excess blasts (MDS-EB)-2, and -EB1 according to the revised 4th edition of the World Health Organization (WHO) classification, respectively. Hierarchical analysis identified four risk groups with distinct survival: (i) MDS-LB, (ii) MDS-EB1/EB2/AML VAF <10%, (iii) MDS-EB1/EB2 VAF ≥10%, and (iv) AML VAF ≥10%. We next evaluated the impact of allelic status, VAF, and complex karyotype (CK). In our cohort, the significance of biallelic status was limited to MDS with <5% blasts and not for blasts 5-9%, as proposed by the International Consensus Classification (ICC), or 5-19%, as proposed by the 5th edition of the WHO (WHO-5). MDS-EB1 and -EB2 with VAF ≥10% had comparable survival (9.6 vs. 7.2 months, P=0.12), regardless of allelic status. Contrary to the ICC proposal, MDS-EB1/EB2 with VAF <10% and CK had poor survival compared to those without CK, comparable to MDS-EB1/EB2 with VAF ≥10% (5.6 vs. 26.2 vs. 6.3 months, P=0.003). Survival of TP53mut AML was poor (median 3.9 months) regardless of allelic/CK status. Thus, utilizing ICC or WHO-5 may underestimate prognosis of MDS with blasts 5-19% and 5-9%, respectively. Collectively, the hierarchical model acknowledges poor survival of 91.9% TP53mut MDS and AML compared to 36.5% and 80.7% by WHO-5 and ICC, respectively.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015238
  2. Am J Hematol. 2025 Mar 13.
    Multihit TP53 Mutations in Myeloproliferative Neoplasms and Acute Myeloid Leukemia: Comparative Analysis of Survival and Risk Factors in 142 Informative Cases.
    Saubia Fathima, Maymona Abdelmagid, Ali Alsugair, Kebede H Begna, Aref Al-Kali, Abhishek A Mangaonkar, Animesh D Pardanani, Mrinal M Patnaik, Cinthya J Zepeda Mendoza, Rong He, Kaaren K Reichard, Talha Badar, James M Foran, Jeanne Palmer, Giuseppe G Loscocco, Paola Guglielmelli, Alessandro M Vannucchi, Attilio Orazi, Daniel A Arber, Devendra Hiwase, Mithun V Shah, Naseema Gangat, Ayalew Tefferi.
      A total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (mTP53MUT) were accessed from the Mayo Clinic database and included (i) chronic phase MPN (MPN-CP; N = 19), (ii) accelerated phase MPN (MPN-AP; N = 14), (iii) blast phase MPN (MPN-BP; N = 28), and (iv) AML (N = 81). Concurrent ASXL1MUT, EZH2MUT, IDH1,MUT and IDH2MUT were more common in MPN-MUTBP-mTP53 compared to AML-mTP53MUT. At median of 11.6 months follow-up, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from the time of mTP53MUT detection, was similar between MPN-BP-mTP53MUT (median 4.6 months) and MPN-AP-mTP53MUT (5.6 months; p = 0.5) but both were inferior to MPN-CP-mTP53MUT (11.6 months, p < 0.01). OS in MPN-CP-mTP53MUT was similar to that of AML-mTP53MUT (median 7.4 months, p = 0.07). In multivariable analysis, OS was favorably affected by ASCT (HR 0.4, p = 0.03) and disease stage (i.e., chronic phase disease) or achieving response to pre-transplant chemotherapy (HR 0.2, p < 0.01) and unfavorably by the presence of concurrent TET2MUT or DNMT3AMUT (HR 2.7, p < 0.01). Based on these risk factors, a 3-tiered risk model was constructed: low (no risk factors; N = 18; median OS 23.8 months); intermediate (one risk factor; N = 44; 11.1 months); and high (two or more risk factors; N = 80; 4 months; p < 0.01). The current study highlights the equally detrimental impact of mTP53MUT on long-term survival in MPN and AML and identifies predictors of short-term survival.
    Keywords:  biallelic TP53; essential thrombocythemia; multihit; myelofibrosis; polycythemia
    DOI:  https://doi.org/10.1002/ajh.27670
  3. Am J Hematol. 2025 Mar 10.
    Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia With Myelodysplasia-Related Genetic Features: Relevance of the Genetic Underlying Category. A Retrospective Analysis on Behalf of the Acute Leukemia Working Party of the EBMT.
    Jordi Esteve, Arnon Nagler, Myriam Labopin, Jurjen Versluis, Jaime Sanz, Tobias Gedde-Dahl, David Burns, Mieke Roeven, Hélène Labussière-Wallet, Peter Von Dem Borne, Gwendolyn Van Gorkom, Nathalie Contentin, Andreas Neubauer, Eva Maria Wagner-Drouet, Nicolaus Kröger, Mohamad Mohty, Fabio Ciceri.
      Patients (pts) with myelodysplasia-related AML (MR-AML) are now genetically recategorized, with three different groups in the International Consensus Classification: AML with mutated TP53 (TP53-AML), with myelodysplasia-related gene mutations (MR-GM AML), and with myelodysplasia-related cytogenetic abnormalities (MR-CG AML). Moreover, TP53-AML is determined by the presence of an additional complex karyotype (TP53-mut CK and non-CK AML, respectively). Nonetheless, the relevance of this classification to transplantation outcomes is largely unknown. We analyzed the outcomes of pts. with MR-AML undergoing allogeneic hematopoietic cell transplantation in first complete remission between 2010 and 2022 according to these genetic categories. Overall, 1152 patients were identified: 379 (33%), 328 (28%), 246 (21%), and 199 (17%) with MR-GM, TP53-mut CK, MR-CG, and TP53-mut non-CK AML, respectively. Median age was 60 years; median year of transplant was 2020. Unrelated donors and reduced-intensity conditioning were used in 65% and 61% of cases, respectively. Outcomes differed markedly among genetic categories, with an increasing relapse incidence (20.2%, 29.2%, 44.6%, and 57.6% at 2 years), and decreasing LFS (60%, 55.3%, 40.6%, and 20.2% at 2 years), overall survival (65.7%, 60.1%, 47.1%, and 24.5% at 2 years), and graft-versus-host disease-free, relapse-free survival (46.9%, 39.5%, 31.9%, and 13.2% at 2 years) in MR-GM, MR-CG, TP53-mut non-CK, and TP53-mut CK AML, respectively. These differences were confirmed in the multivariate analysis (hazard ratio for LFS: 0.21, 0.33 and 0.61 in MR-GM, MR-CG, and TP53-mut non-CK, with respect to reference TP53-mut CK AML group). This study confirms the strong impact of genetic grouping of MR-AML on transplant outcomes.
    Keywords:  acute myeloid leukemia; allogeneic hematopoietic cell transplantation; mutated TP53; myelodysplasia‐related cytogenetic abnormality; myelodysplasia‐related gene mutation
    DOI:  https://doi.org/10.1002/ajh.27647
  4. Nat Commun. 2025 Mar 10. 16(1): 2384
    TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling.
    Yitong Yang, Severine Cathelin, Alex C H Liu, Amit Subedi, Abdula Maher, Mohsen Hosseini, Dhanoop Manikoth Ayyathan, Robert Vanner, Steven M Chan.
      Ten-Eleven Translocation-2 (TET2) mutations drive the expansion of mutant hematopoietic stem cells (HSCs) in clonal hematopoiesis (CH). However, the precise mechanisms by which TET2 mutations confer a competitive advantage to HSCs remain unclear. Here, through an epigenetic drug screen, we discover that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduces the fitness of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs). Mechanistically, we find that TET2 deficiency increases H3K79 dimethylation and expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Correspondingly, TET2 deficiency is associated with a higher proportion of primitive Mpl-expressing (Mpl+) cells in the HSC compartment. Importantly, inhibition of Mpl expression or the signaling downstream of TPO-R is sufficient to reduce the competitive advantage of murine and human TET2-deficient HSPCs. Our findings demonstrate a critical role for aberrant TPO-R signaling in TET2 mutation-driven CH and uncover potential therapeutic strategies against this condition.
    DOI:  https://doi.org/10.1038/s41467-025-57614-y
  5. bioRxiv. 2025 Feb 27. pii: 2025.02.21.639304. [Epub ahead of print]
    CCRL2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53.
    Nour Sabiha Naji, Sergiu Pasca, Theodora Chatzilygeroudi, Pablo Toledano-Sanz, Joseph Rimando, Yashvi Hemani, Brandy Perkins, Xinghan Zeng, Conover Talbot, Bogdan Paun, Abdulmuez Abdulmalik, Chen Lossos, Tatianna R Boronina, Ilias Sinanidis, Panagiotis Tsakiroglou, Priyanka Fernandes, Christopher Esteb, Alexander J Ambinder, Robert N Cole, Rena Xian, Ivana Gojo, Suman Paul, Mark J Levis, Amy E DeZern, Leo Luznik, Styliani Karanika, Linda S Resar, Richard J Jones, Frederick Bunz, Lukasz Gondek, Marios Arvanitis, Theodoros Karantanos.
      Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in AML with erythroid differentiation and TP53 mutations compared to other AML subtypes and healthy hematopoietic cells. The knockout (KO) of CCRL2 suppressed erythroleukemia growth in vitro and in vivo . Further proteomics and transcriptomics analysis revealed IFN-γ signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2 driven IFN-γ signaling independent of exogenous IFN-γ, through phosphorylation of STAT1, via JAK2-dependent and independent mechanisms. CCRL2/IFN-γ signaling is upregulated in erythroid leukemias, and TP53 mutated AML without concurrent increase of IFN-γ secretion in the bone marrow microenvironment and is directly induced by TP53 KO. Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations and highlight CCRL2 as a relevant novel target for these neoplasms.
    One Sentence Summary: CCRL2 is overexpressed in AML with loss-of-function TP53 mutations and erythroid differentiation and promotes IFN-γ signaling response via a cell-intrinsic mechanism.
    DOI:  https://doi.org/10.1101/2025.02.21.639304
  6. Blood Adv. 2025 Mar 14. pii: bloodadvances.2024015335. [Epub ahead of print]
    Factors associated with survival following allogeneic transplantation for myeloid neoplasms harboring TP53 mutations.
    Anmol Baranwal, Kimberly Langer, Vedavyas Gannamani, Danielle Rud, Alia Cibich, Caner Saygin, Mariam T Nawas, Talha Badar, Mohamed A Kharfan-Dabaja, Ernesto Ayala, Vivek Roy, James M Foran, Hemant S Murthy, Madiha Iqbal, Jeanne M Palmer, Lisa Sproat, Saurabh Chhabra, Nandita Khera, Mehrdad Hefazi, Abhishek A Mangaonkar, William J Hogan, Mark R Litzow, Hassan B Alkhateeb, Ayalew Tefferi, Chung Hoow Kok, Guru Subramanian Guru Murthy, Anand A Patel, Ashish Bajel, Devendra K Hiwase, Mithun Vinod Shah.
      Allogeneic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MN) harboring TP53-mutations (TP53mut). The aim of this international study across 7 transplant centers in USA and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype (CK); 94% of TP53 variants were localized to the DNA-binding domain (DBD). Most common co-mutations were ASXL1 (7%), TET2 (7%), and DNMT3A (6%). Median post-HCT survival was 1.03 years and OS at 1-, 2-, and 3-years was 51.4%, 35.1%, and 25.1%, respectively. One-hundred three (76.9%) cases met the International Consensus Classification (ICC) criteria for myeloid neoplasms with mutated TP53 (referred to as ICC-defined TP53mut MN hereafter). 3-year OS of ICC-defined TP53mut was significantly shorter compared to other TP53mut MN (3-year OS 16.9 vs. 54.9%, P=0.002). ICC-defined TP53mut MN was independently associated with inferior OS (HR 2.62, P=0.019). The presence of non-DBD TP53mut only (HR 3.40, P=0.005), DNMT3A co-mutation (HR 2.64, P=0.016), and pre-alloHCT bone marrow blasts ≥5% (HR 2.76, P=0.006) were independently associated with inferior RFS, while melphalan-based conditioning was associated with superior RFS (HR 0.52, P=0.005). Combining these variables, we constructed a hierarchical model that stratified patients into low-, intermediate, and high-risk categories with 1-year RFS of 81.3%, 31.3% and 6.7%, respectively (P<0.001). In conclusion, a subset of MN harboring TP53mut who have low blasts pre-alloHCT and received melphalan-based conditioning derived long-term benefit from alloHCT.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015335
  7. Cell Commun Signal. 2025 Mar 13. 23(1): 135
    Phosphoproteomics identifies determinants of PAK inhibitor sensitivity in leukaemia cells.
    Pedro Casado, Santiago Marfa, Marym M Hadi, Henry Gerdes, Sandra M Martin-Guerrero, Farideh Miraki-Moud, Vinothini Rajeeve, Pedro R Cutillas.
       BACKGROUND: The P21 activated kinases (PAK) are frequently dysregulated in cancer and have central roles in oncogenic signalling, prompting the development of PAK inhibitors (PAKi) as anticancer agents. However, such compounds have not reached clinical use because, at least partially, there is a limited mechanistic understanding of their mode of action. Here, we aimed to characterize functional and molecular responses to PAKi (PF-3758309, FRAX-486 and IPA-3) in multiple acute myeloid leukaemia (AML) models to gain insights on the biochemical pathways affected by these inhibitors in this disease and identify determinants of response in patient samples.
    METHODS: We mined phosphoproteomic datasets of primary AML, and used proteomics and phosphoproteomics to profile PAKi impact in immortalized (P31/Fuj and MV4-11), and primary AML cells from 8 AML patients. These omics datasets were integrated with gene dependency data to identify which proteins targeted by PAKi are necessary for the proliferation of AML. We studied the effect PAKi on cell cycle progression, proliferation, differentiation and apoptosis. Finally, we used phosphoproteomics data as input for machine learning models that predicted ex vivo response in two independent datasets of primary AML cells (with 36 and 50 cases, respectively) to PF-3758309 and identify markers of response.
    RESULTS: We found that PAK1 activation- measured from phosphoproteomics data- was predictive of poor prognosis in primary AML cases. PF-3758309 was the most effective PAKi in reducing proliferation and inducing apoptosis in AML cell lines. In cell lines and primary cells, PF-3758309 inhibited PAK, AMPK and PKCA activities, reduced c-MYC transcriptional activity and the expression of ribosomal proteins, and targeted the FLT3 pathway in FLT3-ITD mutated cells. In primary cells, PF-3758309 reduced STAT5 phosphorylation at Tyr699. Functionally, PF-3758309 reduced cell-growth, induced apoptosis, blocked cell cycle progression and promoted differentiation in a model-dependent manner. ML modelling accurately classified primary AML samples as sensitive or resistant to PF-3758309 ex vivo treatment, and highlighted PHF2 phosphorylation at Ser705 as a robust response biomarker.
    CONCLUSIONS: In summary, our data define the proteomic, molecular and functional responses of primary and immortalised AML cells to PF-3758309 and suggest a route to personalise AML treatments based on PAK inhibitors.
    Keywords:  Acute myeloid leukaemia biomarkers; Cancer; Kinase inhibitors; Lysine demethylase PHF2; Machine learning; PAK inhibitors; PF-3758309; Phosphoproteomics; Proteomics; Target therapy
    DOI:  https://doi.org/10.1186/s12964-025-02107-0
  8. Haematologica. 2025 Mar 13.
    Enforcement of stem-cell dormancy by nucleophosmin mutation is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis.
    Maria Elena Boggio Merlo, Maria Mallardo, Lucilla Luzi, Giulia De Conti, Chiara Caprioli, Roman Hillje, Mario Faretta, Cecilia Restelli, Andrea Polazzi, Valentina Tabanelli, Angelica Calleri, Stefano Pileri, Pier Giuseppe Pelicci, Emanuela Colombo.
      Mutations in the NPM1 gene (NPMc+) and in the FLT3 gene (FLT3-ITD) represent the most frequent co-occurring mutations in Acute Myeloid Leukemia (AML), yet the cellular and molecular mechanisms of their cooperation remain largely unexplored. Using mouse models that faithfully recapitulate human AML, we investigated the impact of these oncogenes on pre-leukemic and leukemic hematopoietic stem cells (HSCs), both separately and in combination. While both NPMc+ and Flt3-ITD promote the proliferation of pre-leukemia HSCs, only NPMc+ drives extended selfrenewal by preventing the depletion of the quiescent HSC pool. Quiescent HSCs exist in a dynamic equilibrium between dormant and active states, which respectively support self-renewal and regenerative haematopoiesis. Transcriptional profiling of these dormant and active states revealed that not only does NPMc+ stimulate the transition from dormancy to activity but it also reinforces the dormant state, thereby ensuring the replenishment of dormant HSCs. Intriguingly, the coexpression of NPMc+ and Flt3-ITD engenders a novel phenotypic state within quiescent HSCs, whereby dormancy and activity co-exist within a single cell. We posit that this unique state fuels the in vivo expansion of self-renewing HSCs and facilitates the rapid selection of leukemiainitiating cells. Pharmacological inhibition of the dormancy-related TGFβ1 - pathway effectively reduces the self-renewal capacity of leukemia SCs and extends survival in our mouse models. Collectively, these findings demonstrate that enforcement of HSC dormancy is a critical determinant of unrestricted self-renewal during leukemogenesis and, as such, represents a compelling target for the development of novel anti-leukemic therapies.
    DOI:  https://doi.org/10.3324/haematol.2024.286577
  9. Blood. 2025 03 11. pii: blood.2024027999. [Epub ahead of print]
    Clonal Hematopoiesis Landscape in Frequent Blood Donors.
    Darja Karpova, Hector Huerga Encabo, Elisa Donato, Silvia Calderazzo, Michael Scherer, Miriam Llorian-Sopena, Aino-Maija Leppä, Roberto Würth, Patrick Stelmach, Despoina Papazoglou, Alessandra Ferrelli, Steven Ngo, Iuliia Kotova, Sabine Harenkamp, Kai Zimmer, Dominik Wolf, Jasper Panten, John Reed, Adriana Przybylla, Torsten Tonn, Annette Kopp-Schneider, Lars Velten, John F DiPersio, Terrence N Wong, Dominique Bonnet, Halvard Bonig, Andreas Trumpp.
      Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 life-time donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FD) compared to sporadic donors (<10 life-time donations, 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex matched control donor (CD) cohorts. Functional analysis of FD enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone which increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with IFNy. Through concurrent mutational and immunophenotypic profiling of primary samples at single cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, while no significant lineage bias was observed in HSCs harboring EPO responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.
    DOI:  https://doi.org/10.1182/blood.2024027999
  10. J Exp Med. 2025 Jun 02. pii: e20240587. [Epub ahead of print]222(6):
    Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system.
    Geunhyo Jang, Rosa Park, Eduardo Esteva, Pei-Feng Hsu, Jue Feng, Samik Upadhaya, Catherine M Sawai, Iannis Aifantis, David R Fooksman, Boris Reizis.
      Leukemia-driving mutations are thought to arise in hematopoietic stem cells (HSC), yet the natural history of their spread is poorly understood. We genetically induced mutations within endogenous murine HSC and traced them in unmanipulated animals. In contrast to mutations associated with clonal hematopoiesis (such as Tet2 deletion), the leukemogenic KrasG12D mutation dramatically accelerated HSC contribution to all hematopoietic lineages. The acceleration was mediated by KrasG12D-expressing multipotent progenitors (MPP) that lacked self-renewal but showed increased proliferation and aberrant transcriptome. The deletion of osteopontin, a secreted negative regulator of stem/progenitor cells, delayed the early expansion of mutant progenitors. KrasG12D-carrying cells showed increased CXCR4-driven motility in the bone marrow, and the blockade of CXCR4 reduced the expansion of MPP in vivo. Finally, therapeutic blockade of KRASG12D spared mutant HSC but reduced the expansion of mutant MPP and their mature progeny. Thus, transforming mutations facilitate their own spread from stem cells by reprogramming MPP, creating a preleukemic state via a two-component stem/progenitor circuit.
    DOI:  https://doi.org/10.1084/jem.20240587
  11. Nat Med. 2025 Mar 10.
    Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial.
    Raajit K Rampal, Sebastian Grosicki, Dominik Chraniuk, Elisabetta Abruzzese, Prithviraj Bose, Aaron T Gerds, Alessandro M Vannucchi, Francesca Palandri, Sung-Eun Lee, Vikas Gupta, Alessandro Lucchesi, Stephen T Oh, Andrew T Kuykendall, Andrea Patriarca, Alberto Álvarez-Larrán, Ruben Mesa, Jean-Jacques Kiladjian, Moshe Talpaz, Joseph M Scandura, David Lavie, Morgan Harris, Sarah-Katharina Kays, Qing Li, Rainer Boxhammer, Barbara Brown, Anna-Maria Jegg, Claire N Harrison, John Mascarenhas.
      Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib-a bromodomain and extraterminal domain (BET) inhibitor-plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50-175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD-25 mg BID permitted). Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response (≥50% reduction in TSS from baseline at week 24). The primary endpoint was met in 65.9% of patients randomized to pelabresib-ruxolitinib (n = 214) versus 35.2% to placebo-ruxolitinib (n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001). Absolute change in TSS was -15.99 versus -14.05 (difference, -1.94; 95% CI, -3.92, 0.04; P = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, -3.5, 15.5) with pelabresib-ruxolitinib versus placebo-ruxolitinib. Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination. Thrombocytopenia and anemia were the most common treatment-emergent adverse events, occurring in 52.8% (13.2% grade ≥3) versus 37.4% (6.1% grade ≥3) and 44.8% (23.1% grade ≥3) versus 55.1% (36.5% grade ≥3), respectively. Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy. ClinicalTrials.gov identifier: NCT04603495 .
    DOI:  https://doi.org/10.1038/s41591-025-03572-3
  12. Am J Hematol. 2025 Mar 10.
    Real-World Outcomes of Relapsed/Refractory Core-Binding Factor Acute Myeloid Leukemia: A COMMAND Registry Study.
    Alexandra E Rojek, Benjamin J McCormick, Joanna Cwykiel, Oluwatobi Odetola, Yasmin Abaza, Nhi Nai, Charles E Foucar, Rohan K Achar, Rory M Shallis, Danielle Bradshaw, Meaghan Standridge, Vamsi Kota, Guru Subramanian Guru Murthy, Talha Badar, Anand A Patel.
      
    Keywords:  AML; AML‐molecular diagnosis and therapy; core‐binding factor; relapsed/refractory
    DOI:  https://doi.org/10.1002/ajh.27664
  13. Haematologica. 2025 Mar 13.
    Impact of hematopoietic cell transplantation and quizartinib in newly diagnosed patients with acute myeloid leukemia and FMS-like tyrosine kinase 3-internal tandem duplications in the QuANTUM-First trial.
    Richard F Schlenk, Pau Montesinos, Hee-Je Kim, Antonio Romero-Aguilar, Radovan Vrhovac, Elżbieta Patkowska, Pavel Žak, Po-Nan Wang, James Hanyok, Li Liu, Yasser Mostafa Kamel, Karima Imadalou, Arnaud Lesegretain, Jorge Cortes, Mikkael A Sekeres, Herve Dombret, Sergio Amadori, Jianxiang Wang, Alexander E Perl, Mark J Levis, Harry P Erba.
      QuANTUM-First (NCT02668653) was a randomized phase 3 trial in newly diagnosed FLT3-ITDQpositive acute myeloid leukemia (AML) patients treated with quizartinib or placebo plus standard induction and consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (allo-HCT), followed by single-agent maintenance therapy. We evaluated the impact of allo-HCT performed in first complete remission (CR1) or composite CR1 (CRc1) on overall survival (OS), considering treatment randomization. Post-hoc extended Cox regression multivariable analyses were conducted in patients who achieved CR/CRc by the end of induction, including allo-HCT in CR1/CRc1 as a time-dependent variable to identify prognostic and predictive factors for OS. There were 297 patients with CR by the end of induction (quizartinib, n=147; placebo, n=150); of these, 157 (52.9%) underwent allo-HCT in CR1 (quizartinib, n=84; placebo, n=73). There were 368 patients with CRc by the end of induction (quizartinib, n=192; placebo, n=176); of these, 196 (53.3%) underwent allo-HCT in CRc1 (quizartinib, n=110; placebo, n=86). Multivariable analyses revealed quizartinib treatment and allo-HCT in either CR1 (hazard ratio [HR]=0.553, 95% confidence interval [CI]=0.383Q0.798, P=0.0015 and HR=0.527, 95% CI=0.349Q0.796, P=0.0023, respectively) or CRc1 (HR=0.645, 95% CI=0.470Q0.886, P=0.0068 and HR=0.557, 95% CI=0.391Q0.793, P=0.0012, respectively) as significant predictive factors for a longer OS. No new safety signals were identified. Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-allo-HCTQrelated complications, mostly grade ≥2 graft-versus-host disease, as expected. This posthoc analysis further supports quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITDQpositive AML patients fit for intensive chemotherapy.
    DOI:  https://doi.org/10.3324/haematol.2024.286623
  14. Clin Lymphoma Myeloma Leuk. 2025 Feb 12. pii: S2152-2650(25)00053-9. [Epub ahead of print]
    SOHO State of the Art Updates and Next Questions Acute Myeloid Leukemia: Current Status and Next Questions.
    Vishrut Shah, Farhad Ravandi.
      Advances in understanding leukemogenesis in acute myeloid leukemia (AML) have led to new drug approvals in the past 4 years. Ongoing preclinical research is expected to produce more targeted therapies, reducing the need for traditional chemotherapy, while also enhancing classification systems and patient prognostication. In newly diagnosed AML, the mainstay of induction still is 7+3 regimen. In unfit adults, combination of venetoclax and hypomethylating agent has emerged to be the standard of care. Introduction of FLT3 inhibitors with the 7 plus 3 regimen has improved outcomes in FLT3 mutant patients. IDH inhibitors have recently been approved for induction in medically unfit adult. Studies focusing on triplet regimen are underway. FLT3 inhibitors and IDH inhibitors have also been approved for Relapsed and Refractory AML. Menin inhibitors are another novel class of drugs which are currently being studied for both de novo as well as relapsed and refractory AML. For consolidation in fit patients, high dose cytarabine and Allogenic transplant are still the mainstay of treatment whenever feasible. FLT3 inhibitors have been studied as long term maintenance after allogenic stem cell transplantation. As potent regimens achieve high-quality remissions, the need for sensitive assays to detect measurable residual disease (MRD) and predict relapse risk will grow. MRD monitoring using flow cytometry and molecular methods have been effective with cytarabine-based treatments and will be crucial for venetoclax therapies. Eradicating MRD is a key goal for AML subsets, with research focused on targeted and immune- based therapies to eliminate MRD and understand relapse through clonal evolution. Allogeneic stem cell transplant is the most effective treatment for residual leukemia in resistant AML but is limited by toxicity and donor availability. Immune-based strategies, including antibodies and bispecific molecules, show promise in early trials, and safer cellular therapies could expand treatment options.
    Keywords:  AML; AML mutations; FLT3 inhibitors; IDH inhibitors; Menin inhibitors
    DOI:  https://doi.org/10.1016/j.clml.2025.02.001
  15. Transplant Cell Ther. 2025 Mar 07. pii: S2666-6367(25)01052-8. [Epub ahead of print]
    Outcome of Patients with IDH-mutated AML following Allogeneic Stem Cell Transplantation - a Retrospective Analysis on behalf of the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy, DRST.
    Thomas Schroeder, Sarah Flossdorf, Claudia Schuh, Caroline Pabst, Michael Stadler, Johannes Schetelig, Claudia Wehr, Matthias Stelljes, Elisa Sala, Andreas Burchert, Julia Winkler, H Christian Reinhardt, Nicolaus Kröger, Katharina Fleischhauer, Christina Rautenberg.
      Mutations in isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are found in 15% to 20% of patients with acute myeloid leukemia (AML). IDH inhibitors have been introduced as targeted treatment and are currently under investigation as maintenance therapy after allogeneic transplantation (allo-SCT). Since reports about the outcome of IDH1- and IDH2-mutated (IDHmut) AML after allo-SCT are limited, we retrospectively analyzed 356 IDH-mutated AML patients (IDH1 40%, IDH2 60%). Ten patients (4%) had received an IDH inhibitor prior transplantation, but none had received maintenance with IDH inhibitors. After a median follow-up of 24 months 3-year probabilities of overall (OS) and event-free (EFS) survival, relapse and non-relapse mortality (NRM) for the entire cohort were 73%, 60%, 27% and 13% respectively. While 3-year OS (78% vs 70%), EFS (56% vs. 63%) and NRM (10% vs 14%) rates were similar for IDH1mut and IDH2mut patients, relapse incidence was numerically higher in IDH1mut patients (34% vs. 24%) and landmark analysis suggested a continuous rise of relapse incidence preferentially in IDH1mut AML also beyond the first year. Concordantly, IDH2 mutation was associated with superior EFS and by trend with lower relapse incidence. The strongest risk factor for adverse outcomes, however, was AML not in CR. This analysis provides benchmarks for interpretation of results emerging from post-transplant maintenance trials in IDHmut AML and suggest that maintenance strategies may further optimize the promising outcome in this molecularly defined subgroup by reducing relapse risk, especially for patients whose AML is not in remission at time of alloHCT.
    Keywords:  AML; IDH mutation; allogeneic transplantation; maintenance; relapse
    DOI:  https://doi.org/10.1016/j.jtct.2025.02.018
  16. Blood. 2025 Mar 11. pii: blood.2024027543. [Epub ahead of print]
    Social Determinants of Health and Access to Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia.
    Natalie Wuliji, Salene M W Jones, Ted A Gooley, Aaron T Gerds, Bruno C Medeiros, Paul J Shami, John P Galvin, Kehinde U A Adekola, Selina M Luger, Maria R Baer, David A Rizzieri, Tanya Wildes, Eunice S Wang, Mikkael A Sekeres, Sudipto Mukherjee, Julie Smith, Mitchell Garrison, Kiarash Kojouri, Jacob S Appelbaum, Mary-Elizabeth M Percival, Brenda M Sandmaier, Stephanie J Lee, Frederick Appelbaum, Rayne H Rouce, Mohamed L Sorror.
      Whether allogeneic hematopoietic cell transplant (allo-HCT) to treat acute myeloid leukemia (AML) is equitably accessible regardless of social determinants of health (SDOH) remains unknown. We examined associations of SDOH with access to allo-HCT and other outcomes. Patients presenting for treatment (n=692) at 13 AML treatment centers were prospectively recruited to a registered clinical trial (#NCT01929408). Various patient, AML, and SDOH specific variables were collected. Outcomes included mortality without allo-HCT, receipt of allo-HCT, and mortality after allo-HCT. Individual multivariable models (Fine-Gray for the first two outcomes, Cox regression for the third) were fit for each SDOH variable, adjusting for relevant patient- and AML-specific variables. Allo-HCT was used to treat 46% of patients. A 10% increase in the proportion with less than a high-school education, in households receiving Supplemental Nutrition Assistance Program, receiving Supplemental Security Income, or in poverty led to modeled adjusted hazard ratios (aHRs) of 1.21 (0.99-1.46), 1.13 (0.97-1.31), 1.41 (1.01-1.97), and 1.16 (0.96-1.39) for death without allo-HCT. The aHRs were 0.67 (0.55-0.83), 0.88 (0.76-1.01), 0.71 (0.48-1.05), and 0.91 (0.75-1.09), for lessened receipt of allo-HCT. Among those who received allo-HCT, aHRs for mortality were 1.18 (0.87-1.60), 1.13 (0.92-1.38), 1.21 (0.81-1.82), and 1.04 (0.79-1.36). Results highlight increased mortality without allo-HCT and decreased access to allo-HCT, but lesser magnitude of increased mortality after allo-HCT, among patients from lower resourced areas due to limited education and/or increased poverty. Targeted interventions and policy changes are needed to ensure that marginalized patient populations have equitable chances for AML cure compared to others.
    DOI:  https://doi.org/10.1182/blood.2024027543
  17. Leukemia. 2025 Mar 11.
    Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F.
    Marc Usart, Quentin Kimmerlin, Jan Stetka, Cédric Stoll, Shivam Rai, Tiago Almeida Fonseca, Riikka Karjalainen, Hui Hao-Shen, Julien Roux, Athimed El Taher, Dylan Lynch, Nikolai Makukhin, Alessio Ciulli, Radek C Skoda.
      Therapy with pegylated interferon alpha (pegIFNα) can induce a deep molecular response in a subset of patients with myeloproliferative neoplasms (MPN). Here we investigated the role of Socs2, a negative regulator of cytokine signaling, in modulating the response to pegIFNα in a JAK2-V617F mouse model of MPN. Deleting Socs2 in JAK2-V617F mice resulted in increased sensitivity to cytokines, without causing significant alterations in the MPN phenotype. When subjected to pegIFNα, the loss of Socs2 enhanced the depletion of JAK2-mutant hematopoietic stem cells (HSCs), evidenced by reduced chimerism in peripheral blood and bone marrow compared to vehicle controls. Additionally, pegIFNα-treated Socs2-deficient JAK2-mutant HSCs exhibited functional impairments in secondary transplantations, reflecting long-term detrimental decline of their stemness. These findings demonstrate that loss of Socs2 enhances the effectiveness of pegIFNα in depleting the JAK2-mutant HSC clone. In line with the genetic ablation of Socs2, the SOCS2 inhibitor MN714 combined with IFNα exhibited better efficacy than IFNα alone in reducing the output of CD34+ cells from PV patients in vitro. Targeting SOCS2 could therefore improve therapeutic responsiveness in MPN patients receiving interferon therapy.
    DOI:  https://doi.org/10.1038/s41375-025-02550-5
  18. Am J Hematol. 2025 Mar 13.
    Allogeneic Stem Cell Transplant for Myelofibrosis and Myelodysplastic Syndromes: A Contemporary Review.
    Nico Gagelmann, Nicolaus Kröger.
      Allogeneic hematopoietic stem-cell transplantation (HCT) remains the only potentially curative therapy for patients with myelodysplastic neoplasms (MDS) and myelofibrosis (MF) and is the standard care for eligible patients with higher-risk disease. Despite significant advancements, both diseases pose unique challenges due to their clinical and molecular heterogeneity, necessitating personalized approaches to patient selection, timing, and transplant management. For MDS, genomic profiling has revolutionized prognostic frameworks such as IPSS-M, enabling tailored therapeutic decisions. In MF, driver mutations (e.g., JAK2, CALR, MPL) and additional high-risk molecular markers provide critical insights into disease biology and transplant outcomes. Optimal timing of HCT is critical, and recent models might help personalize treatment approaches. Molecular measurable residual disease monitoring has demonstrated prognostic value in both diseases, guiding preemptive strategies to mitigate relapse risk. Harnessing molecular technologies, clinical expertise, patient-centered decision-making, and innovative pharmaceutical strategies offers an exciting opportunity to shape a transformative and curative treatment framework. Here, we provide a contemporary review on HCT for MDS and MF, highlighting up-to-date insights into disease biology, standard of care, and recommendations, as well as open avenues.
    Keywords:  busulfan; myelofibrosis; transplantation; treosulfan
    DOI:  https://doi.org/10.1002/ajh.27660
  19. Am J Hematol. 2025 Mar 11.
    TP53-Mutated Myeloid Neoplasms: 2024 Update on Diagnosis, Risk-Stratification, and Management.
    Mithun Vinod Shah, Daniel A Arber, Devendra K Hiwase.
      Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%-12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations (TP53mut) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53mut are more common in older individuals and those with secondary/therapy-related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN-intensive chemotherapy, hypomethylating agents, and the BCL-2 inhibitor venetoclax-do not improve the survival of TP53mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under- or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53mut MN. The development of TP53mut MN is positioned at the intersection of age, hereditary predisposition, and anti-cancer therapies. Precursor TP53mut clones can be detected years prior to the eventual leukemic transformation-raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.
    Keywords:  AML—molecular diagnosis & therapy; myelodysplastic syndrome; neoplasia—myeloid leukemias and dysplasias; p53
    DOI:  https://doi.org/10.1002/ajh.27655
  20. Oncogene. 2025 Mar 13.
    Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import.
    Yuxin Xie, Runlong Zhao, Yingjiao Zheng, Yan Li, Feng Wu, Yufei Lei, Lei Li, Hanqing Zeng, Zhe Chen, Yu Hou.
      Acute myeloid leukemia (AML) represents the most prevalent malignancy within the hematologic system, characterized by refractory relapses and a scarcity of effective treatment options. Karyopherin subunit beta-1 (KPNB1) is a member of karyopherin β family, mediating the nuclear import of its cargoes. In this study, we found that elevated expression levels of KPNB1 are associated with unfavorable outcomes in patients with AML. The knockdown of KPNB1 resulted in growth inhibition and apoptosis in AML cells. Additionally, pharmacological inhibition of KPNB1 using the specific inhibitor importazole (IPZ) significantly reduced tumor burden and prolonged survival in MLL-AF9-induced AML mice. Notably, the inhibition of KPNB1 by IPZ significantly enhanced the sensitivity of both AML cell lines and patient-derived cells to venetoclax in vitro and in xenograft mice models. At the molecular level, we identified an unrecognized cargo of KPNB1, high mobility group 2 (HMGB2), which plays a crucial role in DNA damage repair. Inhibition of KPNB1 resulted in impaired nuclear import of HMGB2, eventually leading to compromised DNA damage repair in AML cells. Overall, our findings elucidate the essential roles of KPNB1 in AML cells through the HMGB2-DNA damage repair axis and highlight a promising therapeutic target for AML intervention.
    DOI:  https://doi.org/10.1038/s41388-025-03340-0
  21. Cancer Res. 2025 Mar 13.
    SMYD3 Activates Fatty Acid β-oxidation to Promote Self-Renewal of Leukemia Stem Cells.
    Min Zhou, Zihao Wu, Fen Wei, Chen Duan, Xiaoying Lin, Waiyi Zou, Chang Liu, Jingxuan Pan, Yanli Jin.
      The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has revolutionized disease management of chronic myeloid leukemia (CML). However, the persistence of leukemia stem cells (LSCs) remains a major barrier to curing CML, highlighting the urgent need to identify the regulators supporting LSCs. In this study, we validated the critical role of the histone methyltransferase SET and MYND domain containing 3 (SMYD3) in the maintenance of LSCs in CML. SMYD3 was overexpressed in CML LSCs and enhanced the survival and self-renewal properties of human primary CD34+ CML cells. Loss of SMYD3 blocked leukemogenesis and impaired the self-renewal and disease reconstitution abilities of LSCs in mice without affecting normal hematopoiesis. SMYD3 stimulated fatty acid β-oxidation (FAO) in LSCs by activating the FABP5/PPARD/CPT1A signaling axis in a methyltransferase activity-dependent manner. Blocking CPT1A-mediated FAO reduced the function of human CML LSCs in vitro and depleted LSCs in vivo. These findings shed light on the role of histone lysine methylation-mediated FAO in the maintenance of LSCs and suggest that SMYD3 may serve as a therapeutic target for treating patients with CML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2117
  22. Cancer Res. 2025 Mar 11.
    In the Right Place and the Right State: Spatial Crosstalk and Immune State Dictate Leukemia Response to Immunotherapy.
    Giorgio Orofino, Cristina Toffalori, Luca Vago.
      Donor Lymphocyte Infusion (DLI) is a crucial therapeutic strategy for relapsed myeloid malignancies post-allogeneic hematopoietic cell transplantation (allo-HCT), leveraging the graft-versus-leukemia (GvL) effect to restore immune control. While highly effective in chronic myeloid leukemia (CML), its efficacy in acute myeloid leukemia (AML) remains limited, with underlying mechanisms not fully understood. Recent research by Maurer and colleagues utilized cutting-edge technologies to dissect immune-leukemia interactions within the bone marrow niche, identifying a cytotoxic CD8+ T cell population as a key mediator of the anti-leukemic response. The study highlights a dynamic expansion of T and NK cells in responders, whereas non-responders display an immune suppressive bone marrow niche. TCR tracking revealed that the primary effectors of GvL in AML originate from the DLI infusion, yet their activation depends on a permissive bone marrow microenvironment. These insights emphasize that leukemia progression and immune response are shaped not only by malignant cells but also by broader niche dynamics. Further investigation is needed to define the different mechanisms that drives response or resistance to cellular therapies, but also to dissect the antigenic specificity of GvL-mediating T cells and define biomarkers predicting response to DLI.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1018
  23. Am J Hematol. 2025 Mar 08.
    Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes.
    Naseema Gangat, Ayalew Tefferi.
      Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin-induced iron-restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF-β)-bone morphogenic protein/sons of mothers against decapentaplegic (BMP-SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.
    Keywords:   JAK2 ; BMP/SMAD; hepcidin; myeloproliferative
    DOI:  https://doi.org/10.1002/ajh.27659
  24. Ann Hematol. 2025 Mar 10.
    Gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia: a regional analysis of COMMODORE in China, South-East Asia, and Russia.
    Bin Jiang, Jian Li, Ligen Liu, Xin Du, Hao Jiang, Jianda Hu, Xiaoxi Zeng, Taishi Sakatani, Masanori Kosako, Yaru Deng, Larisa Girshova, Sergey Bondarenko, Lily Wong Lee Lee, Archrob Khuhapinant, Elena Martynova, Nahla Hasabou, Jianxiang Wang.
      The COMMODORE study demonstrated the efficacy and safety of gilteritinib versus salvage chemotherapy (SC) treatment in a predominantly Asian population with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-mutated(mut+) acute myeloid leukemia (AML); here we present an exploratory analysis of the study stratified by region (China, South-East Asia and Russia). COMMODORE was a Phase 3, open-label, randomized (1:1), multicenter trial. There were 151, 50, and 33 patients in the China, South-East Asia, and Russia cohorts, respectively. Patients treated with gilteritinib had prolonged median overall survival (OS) versus SC-treated patients in all regions (China: 10.0 vs. 5.7 months, HR [95% CI]: 0.614 [0.385, 0.981]; South-East Asia: 7.8 vs. 4.7 months, HR [95% CI]: 0.887 [0.427, 1.843]; Russia: 8.8 vs. 2.6 months, HR [95% CI]: 0.271 [0.111, 0.662]). Improvements in event-free survival (EFS) were observed in the gilteritinib versus SC arms across all cohorts (China: 2.1 vs. 0.8 months; HR [95% CI]: 0.645 [0.427, 0.974]; South-East Asia 2.4 vs. < 0.1 months; HR [95% CI]: 0.415 [0.208, 0.830]; Russia: 6.2 vs. 0.6 months; HR [95% CI]: 0.221 [0.080, 0.614]). Complete remission rates were numerically higher in the gilteritinib versus SC arm across all three regions. Gilteritinib compared with SC treatment improved OS and EFS with no new safety signals, reinforcing the known efficacy and safety profile of gilteritinib in patients with R/R FLT3mut+ AML, and affirming the clinical benefit of gilteritinib in three different patient populations. ClinicalTrials.gov identifier: NCT03182244.
    DOI:  https://doi.org/10.1007/s00277-025-06235-y
  25. Proc Natl Acad Sci U S A. 2025 Mar 18. 122(11): e2412317122
    Periarteriolar niches become inflamed in aging bone marrow, remodeling the stromal microenvironment and depleting lymphoid progenitors.
    Liming Du, Maria Angelica Freitas-Cortez, Jingzhu Zhang, Yuanyuan Xue, Reshma T Veettil, Zhiyu Zhao, Sean J Morrison.
      In early postnatal and young adult bone marrow, Leptin receptor-expressing (LepR+) stromal cells and endothelial cells synthesize factors required for hematopoietic stem cell (HSC) maintenance, including Stem Cell Factor (SCF) and Cxcl12. However, little is known about how these stromal cells change during aging. We performed single-cell RNA sequencing of mouse bone marrow stromal cells at 2, 12, and 24 mo of age. We identified five transcriptionally distinct subsets of LepR+ cells, all of which expressed the highest levels of Scf and Cxcl12 in bone marrow throughout adult life. In aging bone marrow, SCF from LepR+ cells, but not endothelial cells, continued to be necessary for the maintenance of HSCs and early restricted progenitors. However, arteriolar endothelial cells and other periarteriolar cells expressed increasing levels of interferon during aging. This increased the numbers of periarteriolar Sca1+Cxcl9+LepR+ cells with an inflammatory gene signature and depleted lymphoid progenitors, at least some of which are also periarteriolar. The periarteriolar environment thus became particularly inflamed during aging, remodeling the stromal microenvironment and depleting lymphoid progenitors in an interferon-dependent manner.
    Keywords:  hematopoietic stem cell; inflammation; interferon; lymphoid progenitor; niche
    DOI:  https://doi.org/10.1073/pnas.2412317122
  26. bioRxiv. 2025 Mar 02. pii: 2025.02.26.640463. [Epub ahead of print]
    Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.
    Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.
      Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights 1,2 , but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map 3 . Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports de novo purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of de novo purine biosynthesis and identify it as a promising therapeutic target in AML.
    DOI:  https://doi.org/10.1101/2025.02.26.640463
  27. Leukemia. 2025 Mar 12.
    Impact of treatment for adolescent and young adults with essential thrombocythemia and polycythemia vera.
    Yan Beauverd, Jean-Christophe Ianotto, Kyaw Htin Thaw, Marta Sobas, Parvis Sadjadian, Natalia Curto-Garcia, Lee-Yung Shih, Timothy Devos, Dorota Krochmalczyk, Serena Galli, Maria Bieniaszewska, Ilona Seferynska, Mary Frances McMullin, Anna Armatys, Adrianna Spalek, Joanna Waclaw, Mihnea Tudor Zdrenghea, Laurence Legros, Francois Girodon, Krzysztof Lewandowski, Beatriz Bellosillo, Jan Samuelsson, Aitor Abuin Blanco, Pascale Cony-Makhoul, Angela Collins, Chloe James, Rajko Kusec, Marie Lauermannova, Maria Soledad Noya, Malgorzata Skowronek, Lukasz Szukalski, Anna Szmigielska-Kaplon, Marielle Wondergem, Iryna Dudchenko, Joanna Gora-Tybor, Kamel Laribi, Anna Kulikowska de Nałęcz, Jean-Loup Demory, Katell Le Dû, Sonja Zweegman, Carlos Besses Raebel, Radek C Skoda, Stephane Giraudier, Martin Griesshammer, Jean-Jacques Kiladjian, Claire N Harrison.
      Essential thrombocythemia (ET) and polycythemia vera (PV) are rare in adolescent and young adult (AYA). These conditions, similar to those in older patients, are linked with thrombotic complications and the potential progression to secondary myelofibrosis (sMF). This retrospective study of ET and PV patients diagnosed before age 25 evaluated complication rates and impact of cytoreductive drugs on outcomes. Among 348 patients (278 ET, 70 PV) with a median age of 20 years, the of thrombotic events was 1.9 per 100 patient-years. Risk factors for thrombosis included elevated white blood cell count (>11 × 109/L) (HR: 2.7, p = 0.012) and absence of splenomegaly at diagnosis (HR: 5.7, p = 0.026), while cytoreductive drugs did not reduce this risk. The incidence of sMF was 0.7 per 100 patient-years. CALR mutation (HR: 6.0, p < 0.001) and a history of thrombosis (HR: 3.8, p = 0.015) were associated with sMF risk. Interferon as a first-line treatment significantly improved myelofibrosis-free survival compared to other treatments or the absence of cytoreduction (p = 0.046). Although cytoreduction did not affect thrombotic event, early interferon use reduced sMF risk. These findings support interferon use to mitigate sMF risk in AYA ET and PV patients.
    DOI:  https://doi.org/10.1038/s41375-025-02545-2
  28. bioRxiv. 2025 Mar 01. pii: 2025.02.26.640389. [Epub ahead of print]
    Succinate dehydrogenase activity supports de novo purine synthesis.
    Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.
      The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.
    DOI:  https://doi.org/10.1101/2025.02.26.640389
  29. bioRxiv. 2025 Feb 26. pii: 2025.02.20.639296. [Epub ahead of print]
    Influence of Hypoxia on a Biomaterial Model of the Bone Marrow Perivascular Niche.
    Gunnar B Thompson, Victoria R Barnhouse, Sydney K Bierman, Brendan A C Harley.
      Hematopoietic stem cell (HSC) fate is shaped by distinct microenvironments termed niches within the bone marrow. Quiescence, expansion, and differentiation are directly and indirectly regulated by complex combinations of cell secretomes, cell-cell interactions, mechanical signals, and metabolic factors including oxygen tension. The perivascular environment in the bone marrow has been implicated in guiding HSC fate. However, bone marrow presents an environment which is hypoxic (∼1-4% O 2 ) relative to traditional cell culture conditions, and the study of hypoxia in vitro is complicated by the speed with which normoxic conditions during HSC isolation induce differentiation. There is a unique opportunity to use engineered models of the bone marrow to investigate the impact of defined hypoxia on HSC fate. Here, we examine the coordinated impact of oxygen tension and the perivascular secretome upon murine hematopoietic stem and progenitor cells (HSPCs) in vitro. Our findings highlight the importance of mitigating oxygen shock during cell isolation in engineered marrow models. We report a shift toward the Lineage - phenotype with hypoxic culture, expansion of HSPCs in response to perivascular niche conditioned medium, and enhanced HSPC maintenance in a hydrogel model of bone marrow in hypoxic culture when oxygen shock is mitigated during isolation using cyclosporin A.
    DOI:  https://doi.org/10.1101/2025.02.20.639296
  30. Br J Haematol. 2025 Mar 13.
    Monitoring the KMT2A gene post-chemotherapy independently predicts the relapse and survival risk after allogeneic haematopoietic stem cell transplantation.
    Jing Liu, Xiao-Su Zhao, Ying-Jun Chang, Ya-Zhen Qin, Qian Jiang, Hao Jiang, Xiao-Hui Zhang, Lan-Ping Xu, Yu Wang, Meng Lv, Kai-Yan Liu, Xiao-Jun Huang, Xiang-Yu Zhao.
      This study evaluated the kinetics of KMT2A-r during chemotherapy and its impact on allogeneic haematopoietic stem cell transplantation (allo-HSCT) outcomes. KMT2A-r was assessed post-induction (MRD1), after the first (MRD2) and second (MRD3) consolidations and pre-transplant (MRD4) in 52 patients with acute myeloid leukaemia (AML). KMT2A-r significantly decreased from diagnosis to MRD2 (p < 0.001 for diagnosis vs. MRD1; p = 0.019 for MRD1 vs. MRD2). The incidence of KMT2A-r negativity (57.5%) peaked at MRD2. KMT2A-r status at each time point significantly affected post-transplant outcomes. Cluster analysis identified four KMT2A-r kinetic profiles: persistently negative (-/-), turned negative at transplant (+/-), turned positive at transplant (-/+) and persistently positive (+/+). The (-/-) group had the best outcomes, with a cumulative incidence of relapse (CIR) of 13.0%, overall survival (OS) of 82.0% and leukaemia-free survival (LFS) of 81.7%. The (+/+) group had the worst prognosis, with a CIR of 58.8%, OS of 29.4% and LFS of 23.5%. KMT2A dynamics were an independent risk factor for CIR (Hazard ratio [HR] = 11.070, 95%CI 2.395-51.165, p = 0.002), LFS (HR = 9.316, 95%CI 2.656-32.668, p < 0.001) and OS (HR = 7.172, 95%CI 1.999-25.730, p = 0.003). In conclusion, KMT2A-r status after chemotherapy and its kinetics are significant HSCT prognostic indicators.
    Keywords:   KMT2A ; acute myeloid leukaemia; allogeneic haematopoietic stem cell transplantation; measurABLe residual disease; multiparameter flow cytometry
    DOI:  https://doi.org/10.1111/bjh.20036
  31. Am J Hematol. 2025 Mar 14.
    Topics of Interest in Women With Myeloproliferative Neoplasms.
    Natasha Szuber, Paola Guglielmelli, Naseema Gangat.
       OVERVIEW: Sex and gender have emerged as central modifiers of disease biology, phenotype, and clinical outcomes in myeloproliferative neoplasms (MPNs). This review will uniquely highlight issues affecting women with MPN and articulate their relevant determinants.
    EPIDEMIOLOGY AND DIAGNOSIS: A higher overall prevalence of MPN has been established in women. The incidence of essential thrombocythemia (ET) predominates, while, conversely, polycythemia vera (PV) and myelofibrosis (MF) are seen in lower frequencies as compared to men. Diagnostic criteria are dictated by sex-driven physiological variances in hemoglobin and hematocrit levels in PV, mandating separate diagnostic thresholds, respectively: > 16.0 g/dL and > 48% in women vs. > 16.5 and > 49% in men.
    GENETIC FRAMEWORK AND PHENOTYPE: Women with MPN harbor fewer acquired somatic mutations and a lower frequency of high-risk mutations than their male counterparts; lower JAK2V617F driver variant allele frequency and attenuated allele burden kinetics have also been reported. Women with MPN are younger at diagnosis than men and, contingent on subtype, display more indolent disease features. Importantly, validated symptom burden assessments consistently disclose higher scores in women vs. men.
    THROMBOSIS AND OUTCOMES: Women with MPN have a unique thrombotic diathesis with respect to men, more frequently involving the splanchnic venous system in those ultimately diagnosed with PV. Outcomes data depict female sex as a variable associated with more favorable clinical trajectories, including lower rates of MF/leukemic transformation and secondary cancers, as well as improved overall survival rates vis-à-vis men.
    LIFE-CYCLE WINDOWS, PREGNANCY, AND POSTPARTUM: Potential challenges at each significant life stage will be addressed: puberty, preconception and fertility, and perimenopause; these include issues surrounding oral contraceptives and hormone use. Prospective studies suggest overall favorable maternal and fetal outcomes with pregnancy in women with MPN. Full details on risks and reported outcomes will be discussed, as well as a risk-adapted approach to management informed by obstetric and thrombosis history. Recommendations include aspirin 81 mg daily in all patients and cytoreduction with interferon-α in those with antecedent thrombosis, as well as in low-risk cases with higher-risk features (e.g., poorly controlled hematocrit and recurrent fetal loss). Antepartum anticoagulation with low molecular weight heparin (LMWH) is recommended in cases with previous venous thromboembolism.
    CONCLUSIONS AND FUTURE DIRECTIONS: This review highlights female sex and gender as critical drivers of MPN incidence, presentation, and natural history. It further outlines the impact and management of MPN as related to unique female reproductive phases. A sex-informed lens will be required in order to recalibrate current prognostic tools, a requisite to refining patient counselling and clinical decision-making in line with precision medicine. Moreover, while several mechanisms underpinning sex-defined discrepancies have been defined, these mandate further prospective study. Finally, sex and gender-based differences must be weighted in clinical trials with systematized procedures to correct participation imbalances in favor of sex and gender equity.
    Keywords:  MPN; essential thrombocythemia; myelofibrosis; polycythemia vera; women
    DOI:  https://doi.org/10.1002/ajh.27665
  32. Am J Hematol. 2025 Mar 10.
    Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives.
    Giuseppe G Loscocco, Paola Guglielmelli.
      Myelofibrosis (MF) is a myeloproliferative neoplasm that is accompanied by driver JAK2, CALR, or MPL mutations in more than 90% of cases, leading to constitutive activation of the JAK-STAT pathway. MF is a multifaceted disease characterized by trilineage myeloid proliferation with prominent megakaryocyte atypia and bone marrow fibrosis, as well as splenomegaly, constitutional symptoms, ineffective erythropoiesis, extramedullary hematopoiesis, and a risk of leukemic progression and shortened survival. Therapy can range from observation alone in lower-risk and asymptomatic patients to allogeneic hematopoietic stem cell transplantation, which is the only potentially curative treatment capable of prolonging survival, although burdened by significant morbidity and mortality. The discovery of the JAK2 V617F mutation prompted the development of JAK inhibitors (JAKi) including the first-in-class JAK1/JAK2 inhibitor ruxolitinib and subsequent approval of fedratinib, pacritinib, and momelotinib. The latter has shown erythropoietic benefits by suppressing hepcidin expression via activin A receptor type 1 (ACVR1) inhibition, as well as reducing splenomegaly and symptoms. However, the current JAKi behave as anti-inflammatory drugs without a major impact on survival or disease progression. A better understanding of the genetics, mechanisms of fibrosis, cytopenia, and the role of inflammatory cytokines has led to the development of numerous therapeutic agents that target epigenetic regulation, signaling, telomerase, cell cycle, and apoptosis, nuclear export, and pro-fibrotic cytokines. Selective JAK2 V617F inhibitors and targeting of mutant CALR by immunotherapy are the most intriguing and promising approaches. This review focuses on approved and experimental treatments for MF, highlighting their biological background.
    Keywords:  JAK inhibitors; JAK–STAT pathway; disease modification; myelofibrosis; targeted therapies
    DOI:  https://doi.org/10.1002/ajh.27658
  33. Nat Commun. 2025 Mar 07. 16(1): 2287
    Continuous map of early hematopoietic stem cell differentiation across human lifetime.
    Hana Komic, Tessa Schmachtel, Catia Simoes, Marius Külp, Weijia Yu, Adrien Jolly, Malin S Nilsson, Carmen Gonzalez, Felipe Prosper, Halvard Bonig, Bruno Paiva, Fredrik B Thorén, Michael A Rieger.
      Uncovering early gene network changes of human hematopoietic stem cells (HSCs) leading to differentiation induction is of utmost importance for therapeutic manipulation. We employed single cell proteo-transcriptomic sequencing to FACS-enriched bone marrow hematopoietic stem and progenitor cells (HSPCs) from 15 healthy donors. Pseudotime analysis reveals four major differentiation trajectories, which remain consistent upon aging, with an early branching point into megakaryocyte-erythroid progenitors. However, young donors suggest a more productive differentiation from HSPCs to committed progenitors of all lineages. tradeSeq analysis depicts continuous changes in gene expression of HSPC-related genes (DLK1, ADGRG6), and provides a roadmap of gene expression at the earliest branching points. We identify CD273/PD-L2 to be highly expressed in a subfraction of immature multipotent HSPCs with enhanced quiescence. Functional experiments confirm the immune-modulatory function of CD273/PD-L2 on HSPCs in regulating T-cell activation and cytokine release. Here, we present a molecular map of early HSPC differentiation across human life.
    DOI:  https://doi.org/10.1038/s41467-025-57096-y
  34. bioRxiv. 2025 Feb 24. pii: 2025.02.19.638991. [Epub ahead of print]
    RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and WNT pathway activation.
    Madeline Y Mayday, Giulia Biancon, Manyi Wei, Christian Ramirez, Irene Moratti, Andreas P Pintado-Urbanc, Lin Wang, Jether Amos Espinosa, Matthew D Simon, Yaara Ofir-Rosenfeld, Oliver Rausch, Toma Tebaldi, Stephanie Halene, Diane S Krause.
      Acute megakaryoblastic leukemia driven by the RBM15-MKL1 fusion protein (RM-AMKL) is the only known recurrent mutation involving the N6-methyladenosine (m6A) writer complex. Dysregulation of m6A modification affects RNA fate and is linked to oncogenesis. Inhibition of m6A deposition via inhibition of the METTL3 writer protein has anti-tumour activity, but the mechanism underlying its efficacy and cancer specificity remains unclear. We treated murine RM-AMKL cells with a novel METTL3 inhibitor, STM3675, and showed apoptosis in vitro and prolonged survival of mice transplanted with RM-AMKL, implicating m6A as an essential component of AMKL and identifying Wnt signalling as a key driver of leukemogenesis. To elucidate the mechanism by which m6A contributes to leukemogenesis we employed a multi-omic approach, combining transcriptome-wide assessment of RNA binding, methylation and turnover. We show for the first time that RM retains the RNA-binding and m6A-modifiying functions of its RBM15 component, while also selectively regulating distinct mRNA targets, particularly genes involved in Wnt signalling including Frizzled. Frizzled genes are upregulated by RM and downregulated in RM-AMKL cells in response to METTL3 inhibition, providing an m6A-dependent explanation for their upregulation. Direct Frizzled knockdown reduced RM-AMKL growth, which was partially rescued by treatment with a β-catenin agonist, underscoring a functional role of Wnt signalling in RM-AMKL. Human AMKLs show elevated Wnt pathway and Frizzled gene expression, highlighting the relevance of our work. Together, our findings reveal that RM-specific m6A modifications and activation of Wnt signalling are critical drivers of RM-AMKL, highlighting these pathways as potential therapeutic targets.
    Key Points: RM retains functional abilities of RBM15 and additionally interacts with Wnt-related transcripts to increase expression of Fzd proteins.The METTL3 writer complex and WNT signalling pathways are essential for RM-driven leukemia.
    DOI:  https://doi.org/10.1101/2025.02.19.638991
  35. Leukemia. 2025 Mar 12.
    Comparison of subcutaneous injection versus intravenous infusion of cytarabine for induction therapy in adult acute myeloid leukemia.
    Huafeng Wang, Shanshan Suo, Dengju Li, Jianyong Li, Lu Liu, Ying Lu, Jianping Shen, Chunyan Ji, Tong Chen, Kang Yu, Hanyun Ren, Yan Li, Ying Chen, Shaolei Zang, Bin Liang, Sijing Kang, Jinghan Wang, Wei Cheng, Wenjuan Yu, Haitao Meng, Hongyan Tong, Jie Jin.
      
    DOI:  https://doi.org/10.1038/s41375-025-02556-z
  36. Hemasphere. 2025 Mar;9(3): e70097
    Cell-free DNA for detection and monitoring of extramedullary AML relapse.
    Henri C Hupe, Clara P Wienecke, Stephan Bartels, Elisa Schipper, Jannika Leßmann, Alina Lasch, Maximilian Bader, Razif Gabdoulline, Martin Neugebohren, Elke Dammann, Hans H Kreipe, Ulrich Lehmann, Anke K Bergmann, Nataliya Di Donato, Michael Stadler, Matthias Eder, Arnold Ganser, Florian H Heidel, Felicitas Thol, Michael Heuser.
      Isolated extramedullary manifestations (IEM) of acute myeloid leukemia (AML) are recurrent events, especially following allogeneic hematopoietic cell transplantation (alloHCT). To date, measurable residual disease (MRD) assessment for this difficult-to-treat patient cohort has not been established. In this study, we evaluated highly sensitive next-generation sequencing (NGS) of IEM-AML tumor and compared it with cell-free DNA (cfDNA) from plasma, as well as highly sensitive NGS analysis of bone marrow mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC), in a cohort of 15 IEM-AML patients with 19 IEM-AML episodes. cfDNA demonstrated a superior representation of IEM-AML tumor mutations compared to BMMC or PBMC, with a median variant allele frequency (VAF) of 0.8% and a mutation detection rate of 62% (37 of 60 mutations), compared to a median VAF of 0.05% and detection rate of 27%, respectively (16 of 60 mutations, p < 0.01). Among 44 mutations identified in 14 IEM-AML relapse tumors, 30 mutations (68%) were known from initial diagnosis. Using diagnostic mutations from initial diagnosis for MRD analysis and detection of IEM-AML relapse, 16 of 17 IEM-AML relapse episodes were detected via cfDNA, whereas only 7 of 17 were identified using conventional analysis of BMMC or PBMC. Our findings demonstrate that cfDNA analysis from plasma effectively captures the molecular profile of IEM-AML. More than one-third of clinically relevant mutations were exclusively detected through cfDNA and were missed by conventional NGS-MRD of BMMC or PBMC. These results suggest that MRD monitoring using cfDNA offers a more comprehensive and sensitive approach to detecting IEM-AML relapse compared to standard methods.
    DOI:  https://doi.org/10.1002/hem3.70097
  37. Leuk Lymphoma. 2025 Mar 11. 1-4
    Efficacy of first-line tagraxofusp in blastic plasmacytoid dendritic cell neoplasm with prior or concomitant hematologic malignancy: subgroup analysis of a pivotal trial.
    Naveen Pemmaraju, Marina Konopleva, Kendra L Sweet, Anthony S Stein, David A Rizzieri, Eunice S Wang, Sumithira Vasu, Todd L Rosenblat, Alessandra Tosolini, Ira Gupta, Andrew A Lane.
      
    Keywords:  CD123; Tagraxofusp; blastic plasmacytoid dendritic cell neoplasm; hematologic malignancies; phase1/2; prior/concomitant
    DOI:  https://doi.org/10.1080/10428194.2025.2475338
  38. Cell Signal. 2025 Mar 11. pii: S0898-6568(25)00148-2. [Epub ahead of print] 111735
    OTUB1 promotes the progression of acute myeloid leukemia by regulating glycolysis via deubiquitinating c-Myc.
    Yang Liao, Liang Zhong, Yi Zhao, Peng Wan, Ying Zhang, Ying Deng, Hongyan Zhang, Meng Wang, Beizhong Liu.
      Acute myeloid leukemia (AML) is the most common type of adult leukemia and patients with AML often have poor prognosis, for which there remains an urgent need to identify novel selective targeted therapy. OTUB1, a deubiquitinating enzyme, is associated with the malignant progression of multiple cancers. However, the role of OTUB1 in AML is still unclear and warrants further investigations. Our study revealed that the expression of OTUB1 is significantly upregulated in AML. Next, we observed that knockdown of OTUB1 inhibits AML cell proliferation and promotes AML cell apoptosis and G0/G1 phase blockade using CCK-8 assay, western blotting, and flow cytometry. Mechanistically, OTUB1 drives the malignant development of AML through regulating cellular aerobic glycolysis by deubiquitinating c-Myc. Lastly, by investigating whether inhibition of OTUB1 enhances the sensitivity of chemotherapeutic agents commonly used in the clinical treatment of AML, we found that combining OTUB1 inhibition with daunorubicin treatment could achieve better therapeutic effects in AML. In brief, our results revealed a novel mechanism by which OTUB1 promotes glycolysis via deubiquitinating c-Myc in AML. Consequently, targeting OTUB1 may provide a promising strategy for enhancing the efficacy of AML treatment.
    Keywords:  Acute myeloid leukemia; Daunorubicin; Glycolysis; OTUB1; c-Myc
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111735
  39. Am J Hematol. 2025 Mar 12.
    Impact of Donor Age and Donor Cytomegalovirus Serostatus on Outcomes After Related Donor Allogeneic Hematopoietic Stem Cell Transplantation.
    Rohtesh S Mehta, Hannah Choe, Jennifer Saultz, Zimu Gong, Prashant Sharma, Taha Al-Juhaishi, Gabriela S Petitto, Aleksandr Lazaryan, Anurag Singh, Elisabetta Xue, Dimana Dimitrova, Mustafa Hyder, Shannon McCurdy, Annie Im, Bryan Huber, Yosra M Aljawai, Jennifer Kanakry, Filippo Milano, Christopher G Kanakry.
      Cytomegalovirus (CMV) infection post-hematopoietic cell transplantation (HCT) remains a significant cause of morbidity and mortality. While letermovir prophylaxis is available for CMV-seropositive recipients, optimal donor selection for CMV-seronegative recipients remains unclear, with donor age often prioritized over CMV serostatus. We investigated the relative impact of donor age and CMV serostatus in CMV-seronegative recipients (n = 1013) with either CMV-seropositive (n = 318) or CMV-seronegative donors (n = 695), who underwent HCT with HLA-matched sibling donors with calcineurin inhibitor-based or post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis, or haploidentical donors with PTCy. Multiple conventional and machine-learning approaches were employed to account for confounding factors. Across all analyses, CMV-seropositive donor status was consistently associated with significantly inferior overall survival (OS) and disease-free survival, primarily driven by increased non-relapse mortality (NRM). Older donor age showed a statistically significant association with OS and DFS in some but not all models, and its effect size was small (about 1% increased hazard per year in Cox proportional hazard model) compared to the substantial impact of CMV-seropositive donors (about 27%-33% increased hazards for worse OS, approximately 50%-60% higher NRM in Cox proportional hazard model). However, our machine learning model revealed a more nuanced and complex non-linear effect of donor age, further demonstrating the adverse impact of donor CMV serostatus. Our findings suggest that prioritizing a CMV-seronegative donor may be associated with improved outcomes in CMV-seronegative recipients. Further research is needed to validate these findings and explore underlying mechanisms.
    Keywords:  CMV; CNI; HLA matched sibling donor; Haploidentical; PTCy; calcineurin inhibitor; cytomegalovirus; donor age; post‐transplantation cyclophosphamide
    DOI:  https://doi.org/10.1002/ajh.27662
  40. Blood Adv. 2025 Mar 14. pii: bloodadvances.2024015621. [Epub ahead of print]
    Mature Megakaryocytes Acquire Immune Characteristics in a Mouse Model of Aplastic Anemia.
    Ashvind Anand Prabahran, Liangliang Wu, Ash Lee Manley, Zhijie Wu, Shouguo Gao, Hiroki Mizumaki, Valentina Baena, Zulfeqhar A Syed, Christian A Combs, Jichun Chen, Xingmin Feng, Neal S Young.
      Megakaryocytes (MKs) serve diverse roles beyond platelet production, including hematopoietic stem cell maintenance and immune response modulation. In our mouse model of immune bone marrow failure (BMF), we observed the unexpected persistence of MKs despite thrombocytopenia. These MKs exhibited heightened expression of immune activation markers, such as IA-IE and CD53, compared to MKs from healthy controls. Single-cell RNA sequencing analysis (scRNA-seq) revealed upregulation of immune response pathways and downregulation of pathways related to platelet function and homeostasis in MKs from marrow failure animals. Electron microscopy demonstrated that these MKs had fewer cytoplasmic extensions, reduced a-granules, and a less developed demarcation membrane system. MKs from BMF animals had reduced ability to produce platelets compared to normal control MKs. Interestingly, when coculture with BMF-derived T cells, MKs from healthy mice acquired immune characteristics. Functionally, MKs from BMF mice suppressed hematopoietic stem cell colony formation in coculture experiments. Mechanistically, these MKs appeared to act as antigen-presenting cells, capable of T cell activation. Notably, similar immune activation of MKs was observed in aplastic anemia patients through scRNA-seq. These findings highlight the immune functions of mature MKs in an alloimmune model of BMF, with potential implications for human aplastic anemia and related hematologic disorders.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015621
  41. Am J Hematol. 2025 Mar 08.
    Classification of Myelodysplastic, Myeloproliferative, and Myelodysplastic/Myeloproliferative Neoplasms: The Past, Present, and Future.
    Daniel A Arber, Attilio Orazi.
      With the recent publication of new classification systems of hematopoietic neoplasms, understanding how recognition of disease entities has occurred over time and the subsequent development of formal disease classifications is of importance. This review focuses on the early recognition of myeloid disorders, especially chronic myeloid disorders, and how clinical observations became associated with specific cytologic, histologic, immunophenotypic, and eventually genetic features. This combined approach to disease classification is of particular importance in the evaluation of chronic myeloid neoplasms and has resulted in the definition of clinicopathologic disease entities that allow for more customized treatment approaches. The constant incorporation of ever-increasing information related to these disorders illustrates that disease classification is a constantly evolving process that requires constant updates as we strive to better understand the disorders we diagnose and treat.
    Keywords:  classification; myelodysplastic syndrome; myelodysplastic/myeloproliferative neoplasms; myeloproliferative neoplasms
    DOI:  https://doi.org/10.1002/ajh.27656
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