bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–05–11
thirty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Characteristics and outcomes of newly diagnosed acute myeloid Leukemia with KMT2A rearrangements.
  2. Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort.
  3. Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study.
  4. BLAST: A Globally Applicable and Molecularly Versatile Survival Model for Chronic Myelomonocytic Leukemia.
  5. Pivotal Results of SELECT-MDS-1 Phase 3 Study of Tamibarotene with Azacitidine in Newly Diagnosed Higher-Risk MDS.
  6. Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.
  7. Momelotinib in JAK2 inhibitor-naïve myelofibrosis: pros and cons.
  8. Clec12a is required for the pathogenesis of NUP98::NSD1 AML.
  9. Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants.
  10. Splicing regulatory dynamics for precision analysis and treatment of heterogeneous leukemias.
  11. ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis.
  12. m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
  13. Outcomes With Venetoclax 50 mg, Hypomethylating Agents, and Voriconazole or Posaconazole in Acute Myeloid Leukemia.
  14. Ciclosporin A potentiates venetoclax efficacy in FLT3-ITD AML by targeting the NFATC1-AKT-mTOR-BCL-2/MCL-1 signaling axis.
  15. Dose reduced induction therapy (A)-AIDA in patients with AML, being unfit for standard 7+3 chemotherapy and Literature Review of AML treatment in unfit/older AML patients.
  16. Asciminib remained superior vs bosutinib in late-line CML-CP after nearly 4 years of follow-up in ASCEMBL.
  17. Analysis of the effects of statin therapy on clonal dynamics in clonal haematopoiesis of indeterminate potential: insights from the English Longitudinal Study of Ageing.
  18. Myelodysplastic neoplasms with ring sideroblasts without SF3B1 mutations in adults: enrichment of germline variants in congenital sideroblastic anemia genes.
  19. PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via p53-mediated degradation.
  20. Emerging Therapeutic Approaches for Anemia in Myelofibrosis.
  21. Age-stratified machine learning identifies divergent prognostic significance of molecular alterations in AML.
  22. Regulation of H3K4me3 breadth and MYC expression by the SETD1B catalytic domain in MLL-rearranged leukemia.
  23. ANKRD26-related Thrombocytopenia 2 with a Baseline Increase in Blasts: Implications for Clinical Surveillance.
  24. Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F- positive MPNs in vivo.
  25. How to use luspatercept and erythropoiesis-stimulating agents in low-risk myelodysplastic syndrome.
  26. Phase 1/2 Study of High-Dose Palifermin for GVHD Prophylaxis in Patients Undergoing HLA-Matched Unrelated Donor HCT.
  27. Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations.
  28. The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.
  29. Event-free survival in early polycythemia vera patients correlates with molecular response to ropeginterferon alfa-2b or hydroxyurea/best available therapy (PROUD-PV/CONTINUATION-PV).
  30. Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.
  1. Leukemia. 2025 May 09.
    Characteristics and outcomes of newly diagnosed acute myeloid Leukemia with KMT2A rearrangements.
    Alex Bataller, Hannah E Goulart, Ghayas C Issa, Courtney D DiNardo, Naval Daver, Tapan Kadia, Alexandre Bazinet, Ian M Bouligny, Jayastu Senapati, Fadi G Haddad, Gautam Borthakur, Koji Sasaki, Nicholas J Short, Musa Yilmaz, Guillermo Montalban-Bravo, Guiling Tang, Sanam Loghavi, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Elias Jabbour.
      Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar) has poor outcomes. We analyzed 1,611 patients with AML and 4.3% demonstrated rearrangements in KMT2A. Signaling-related genes (NRAS 30%, KRAS 23% and FLT3-TKD 16%) were the most frequently mutated in patients with KMT2Ar AML. Patients treated with intensive chemotherapy (IT) achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) rate of 81%, and when combined with venetoclax, the CR/CRi rate increased to 100%. Patients treated with low intensity treatment (LIT) achieved an CR/CRi rate of 33%, and when combined with venetoclax, the CR/CRi rate was 61%. For patients treated with IT, the 5-year overall survival (OS) and event-free survival (EFS) rates were 66% and 64%, respectively, compared with 7% in those treated with LIT. Thirty-nine patients (57%) underwent allogeneic stem cell transplantation after achieving CR/CRi. For patients treated with LIT, multivariate analysis demonstrated that N/KRAS mutations were predictive for OS (HR 2.93, 95% CI 1.18-7.29, P = 0.021) and EFS (HR 3.51, 95% CI 1.35-9.24, P = 0.01). In summary, outcomes in KMT2Ar AML have improved over years in patients treated with IT, whereas those treated with LIT continue to show poor survival, highlighting the need for novel combinations.
    DOI:  https://doi.org/10.1038/s41375-025-02634-2
  2. Blood Cancer J. 2025 May 07. 15(1): 88
    Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort.
    Mithun Vinod Shah, Kevin Hung, Anmol Baranwal, Gauri Wechalekar, Aref Al-Kali, Carla R Toop, Patricia Greipp, Monika M Kutyna, Aasiya Matin, Dariusz Ladon, Antoine Saliba, Dong Chen, Kebede Begna, Anna Brown, Danielle Rud, Mark R Litzow, William J Hogan, Peter Bardy, Talha Badar, Sharad Kumar, David T Yeung, Mrinal M Patnaik, James M Foran, Rong He, Naseema Gangat, Mehrdad Hefazi, Hamish S Scott, Cecilia Y Arana Yi, Hassan Alkhateeb, Abhishek A Mangaonkar, Daniel Thomas, Christopher N Hahn, Attilio Orazi, Daniel A Arber, Chung Hoow Kok, Ayalew Tefferi, Devendra Hiwase.
      The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53mut) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53mut (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53mut MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53mut acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v) TP53mut VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53mut AML was associated with significantly poor survival compared to TP53-wild type TP53wt AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53mut MN as a distinct subentity. Secondly, the survival of TP53mut with blast 10-19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53mut with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53mut AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53mut MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.
    DOI:  https://doi.org/10.1038/s41408-025-01290-0
  3. Blood. 2025 May 07. pii: blood.2025028357. [Epub ahead of print]
    Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study.
    Martha L Arellano, Michael J Thirman, John F DiPersio, Mael Heiblig, Eytan M Stein, Andre C Schuh, Andrius Zucenka, Stéphane De Botton, Carolyn S Grove, Gabriel N Mannis, Cristina Papayannidis, Alexander E Perl, Ghayas C Issa, Ibrahim Aldoss, Ashish Bajel, David S Dickens, Michael W M Kühn, Ioannis Mantzaris, Emmanuel Raffoux, Elie Traer, Irina Amitai, Hartmut Döhner, Corinna Greco, Tibor J Kovacsovics, Christine M McMahon, Pau Montesinos, Arnaud Pigneux, Paul J Shami, Richard M Stone, Ofir Wolach, John G Harpel, Yakov Chudnovsky, Li Yu, Rebecca G Bagley, Angela R Smith, James S Blachly.
      The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary endpoints were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR+CRh), and safety and tolerability. Secondary endpoints included overall response rate (ORR) and duration of response. As of September 18, 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 prior lines of therapy, 35.9%; prior venetoclax, 75.0%). The CR+CRh rate was 23.4% (1-sided P=.0014); the ORR was 46.9%. Median duration of CR+CRh was 4.7 months. Five of 30 responders (16.7%) proceeded to hematopoietic stem cell transplant (HSCT); 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as NCT04065399.
    DOI:  https://doi.org/10.1182/blood.2025028357
  4. Blood. 2025 May 07. pii: blood.2024027170. [Epub ahead of print]
    BLAST: A Globally Applicable and Molecularly Versatile Survival Model for Chronic Myelomonocytic Leukemia.
    Ayalew Tefferi, Saubia Fathima, Maymona Abdelmagid, Ali Alsugair, Fnu Aperna, Mahsa Rezasoltani, Muhammad Yousuf, Anuya Natu, Clifford M Csizmar, Mark Gurney, Terra L Lasho, Christy M Finke, Rashmi Kanagal-Shamanna, Danielle Hammond, Kelly Sharon Chien, Alexandre Bazinet, Courtney D DiNardo, Tapan M Kadia, Abhishek A Mangaonkar, Naval G Daver, Animesh D Pardanani, Gautam Borthakur, Cinthya J Zepeda-Mendoza, Kaaren K Reichard, Rong He, Sanam Loghavi, Francesco Passamonti, Farhad Ravandi, Koji Sasaki, Dirk Larson, Guillermo Garcia-Manero, Francesco Onida, Naseema Gangat, Guillermo Montalban-Bravo, Mrinal M Patnaik.
      We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to "BLAST": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being "favorable" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, "unfavorable". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.
    DOI:  https://doi.org/10.1182/blood.2024027170
  5. Blood Adv. 2025 May 07. pii: bloodadvances.2025016229. [Epub ahead of print]
    Pivotal Results of SELECT-MDS-1 Phase 3 Study of Tamibarotene with Azacitidine in Newly Diagnosed Higher-Risk MDS.
    Amy E DeZern, Sylvain Thepot, Stéphane De Botton, Andrea Patriarca, Dries Deeren, Jose Miguel Torregrose Diaz, Giovanni Marconi, Teresa Bernal Del Castillo, Juan Miguel Bergua Burgues, Blanca Xicoy, Anna Jonasova, Amer M Zeidan, Sophie Dimicoli-Salazar, Célestine Simand, David Valcárcel, María Díez-Campelo, Wanxing Chai-Ho, Lalit Saini, Alice Garnier, Klaus Geissler, Yishai Ofran, Zsolt Nagy, Pramila Krishnamurthy, Michael Lübbert, Grzegorz W Basak, Hetty E Carraway, David A Sallman, Uma Borate, Valeria Santini, Victoria Campbell, Pierre Fenaux, Thorsten Braun, Francesco Lanza, Jan Maciej Zaucha, David A Roth, Sofia Paul, Pourab Roy, Michael Kelly, Angela Volkert, Jaime Chisolm, Tanya Abdul Malak, Virginia Klimek, Thomas Cluzeau.
      Higher-risk MDS (HR-MDS) with RARA gene overexpression is a subset of HR-MDS patients (pts) with an actionable target for tamibarotene, an oral and selective RARα agonist. Tamibarotene in combination with azacitidine (AZA) showed high complete remission (CR) rates in AML. SELECT-MDS-1 (NCT04797780) was a Phase 3 study comparing the activity of tamibarotene/ azacitidine (AZA) to placebo/AZA in newly diagnosed (ND) HR-MDS pts with RARA overexpression. Eligible patients had confirmed RARA overexpression by blood-based assay, untreated MDS with higher-risk features by IPSS-R and a bone marrow blast count >5%. Patients were randomized 2:1 to receive either tamibarotene/AZA or placebo/AZA, respectively. A total of 246 participants with HR-MDS and RARA overexpression were randomized with 164 and 82 in the tamibarotene/azacitidine and placebo/azacitidine groups, respectively. Baseline characteristics included: 69.9% male; median age 75 (38-93); primary MDS 89.8%; WHO 2016 classification MDS-EB-1 48%, MDS-EB-2 52%; median bone marrow blasts 9.0%; IPSS-R risk category intermediate (25.5%), high (35.7%), very high (38.9%). The study did not meet the primary endpoint of CR, with a p-value of 0.2084 for the treatment effect in the tamibarotene/AZA group compared to the placebo/AZA group. The CR rates were 23.81% and 18.75% in the tamibarotene/AZA and placebo/AZA groups, respectively. The use of tamibarotene-based therapy to target RARα as a novel approach in HR-MDS pts with RARA gene overexpression is not a paradigm which can augment response rates beyond HMA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016229
  6. Clin Cancer Res. 2025 May 06.
    Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.
    Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff.
       PURPOSE: Acute myeloid leukemia (AML) is characterized by frequent mutation of fms-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. Here, we investigated the antileukemia efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3-internal tandem duplication (ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase 1 clinical trial.
    METHODS: Preclinical studies used human and murine cell lines carrying FLT3-ITD, and/or TKD mutations and TP53 WT/knockdown, leukemia cell xenograft models and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2i (DS-5272). An open-label, phase 1, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.
    RESULTS: Dual inhibition of FLT3-ITD and MDM2 synergistically induced apoptosis in FLT3-ITD/TP53 WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of FLT3-ITD AML. Phase 1 clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of relapsed/refractory AML patients. Unsupervised single-cell proteomics analysis showed Q/M treatment decreased the expression of prosurvival (pERK, pAKT, Mcl-1) proteins and activated protein signaling downstream of p53 including PUMA. YTHDF2 was increased post therapy in resistant cells. Q/M combination demonstrated higher activity in CD34+ versus CD34- leukemia blasts.
    CONCLUSIONS: Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2764
  7. Blood Cancer J. 2025 May 07. 15(1): 91
    Momelotinib in JAK2 inhibitor-naïve myelofibrosis: pros and cons.
    Naseema Gangat, Ayalew Tefferi.
      
    DOI:  https://doi.org/10.1038/s41408-025-01302-z
  8. Blood Adv. 2025 May 07. pii: bloodadvances.2024015739. [Epub ahead of print]
    Clec12a is required for the pathogenesis of NUP98::NSD1 AML.
    Sagarajit Mohanty, Fiorella Charles Cano, Razif Gabdoulline, Courteney K Lai, Basem Othman, Harish Sudarsanam, Thomas Eder, Florian Grebien, Daniel B Lipka, Reinhard Henschler, Michael Heuser.
      NUP98::NSD1 is one of the most recurring nucleoporin 98 (NUP98) fusions in acute myeloid leukemia (AML). NSD1-driven AML is associated with adverse outcomes and poor response to conventional treatments. However, limited studies have been done to identify new potential targets to develop better treatment approaches. The C-type lectin domain family 12, member A (CLEC12A) is a cell surface receptor that is differentially expressed in leukemic stem cells (LSCs) compared to healthy hematopoietic stem cells (HSCs). We demonstrated a strong overexpression of CLEC12A in both NUP98::NSD1 patients and murine AML cells transformed with NUP98::NSD1. To understand the role of Clec12a in NUP98::NSD1 AML, we depleted Clec12a expression in NUP98::NSD1+NRASG12D immortalized cells using the CRISPR/Cas9 approach. NUP98::NSD1+NRASG12D/Clec12a knockout cells showed higher levels of apoptosis and lower colony numbers in vitro compared to NUP98::NSD1+NRASG12D/Clec12a wildtype cells. Importantly, the deletion of Clec12a significantly reduced leukemic engraftment and prolonged survival of the NUP98::NSD1+NRASG12D murine model. Our data suggest to further explore CLEC12A as a potential target for the treatment of NUP98::NSD1 AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015739
  9. Leukemia. 2025 May 07.
    Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants.
    Ryan J Stubbins, Stephen Arnovitz, Jennie Vagher, Anase Asom, Melody Perpich, Madeline Pies, Imo J Akpan, Edward Chew, Joshua Bridgers, Aly Karsan, Courtnee Rodgers, Ashwin Koppayi, Hatice Basdag, Michael W Drazer, Soma Das, Jason Cheng, Afaf E G Osman, Lucy A Godley.
      The role of germline CHEK2 variants in hematopoietic malignancies (HMs) is poorly understood. We examined pathogenic/likely pathogenic (P/LP) CHEK2 variants in patients with hereditary HMs (HHMs), a solid tumor risk cohort, public datasets, and a knock-in mouse model. In the HHM cohort, 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68-10.73, P < 0.001). In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history. A genome wide association study showed enrichment of CHEK2 loss-of-function variants with myeloid leukemia (P = 5.78e-7). In public acute myeloid leukemia (AML) datasets, 1% (16/1348) of patients had P/LP CHEK2 variants. In a public myelodysplastic neoplasms (MDS) dataset, 2% (5/214) had P/LP CHEK2 variants. Chek2 p.I161T mice, homologous to human p.I157T, had worse survival as heterozygotes (P = 0.037) or homozygotes (P = 0.005), with fewer Lin-CD34+ and Lin-cKit+ cells. Our data suggest P/LP CHEK2 variants are HHM risk alleles.
    DOI:  https://doi.org/10.1038/s41375-025-02635-1
  10. Sci Transl Med. 2025 May 07. 17(797): eadr1471
    Splicing regulatory dynamics for precision analysis and treatment of heterogeneous leukemias.
    Meenakshi Venkatasubramanian, Leya Schwartz, Nandini Ramachandra, Joshua Bennett, Krithika R Subramanian, Xiaoting Chen, Shanisha Gordon-Mitchell, Ariel Fromowitz, Kith Pradhan, David Shechter, Srabani Sahu, Diane Heiser, Peggy Scherle, Kashish Chetal, Aishwarya Kulkarni, Davy Lee, Jeff Zhou, Kasiani C Myers, Elizabeth Tseng, Matthew T Weirauch, H Leighton Grimes, Daniel T Starczynowski, Amit Verma, Nathan Salomonis.
      The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations remains poorly understood. Prompted by the finding that splicing uniquely resolved genetic subtypes of cancer, we developed an unsupervised computational workflow called OncoSplice to comprehensively define tumor molecular landscapes. In adult and pediatric acute myeloid leukemia (AML), OncoSplice identified the spectrum of driver genetics from splicing profiles alone, defined more than a dozen previously unreported molecular subtypes recurrent across AML cohorts, and discovered a dominant splicing subtype that partially phenocopies U2AF1-mutant splicing. Although pediatric leukemias lack splicing factor mutations, this U2AF1-like subtype similarly spanned pediatric and adult AML genetics and consistently predicted poor prognosis. Using long-read single-cell RNA sequencing, we confirmed that discovered U2AF1-like splicing was shared across cell states, co-opted a healthy circadian gene program, was stable through relapse, and induced a leukemic stem cell program. Pharmacological inhibition of an implicated U2AF1-like splicing regulator, PRMT5, rescued leukemia missplicing and inhibited leukemic cell growth. Finally, genetic deletion of IRAK4, a common target of U2AF1-like and PRMT5 treatment, blocked leukemia development in xenograft models and induced differentiation. This work suggests that broad splicing dysregulation, in the absence of select mutations, is a therapeutic target in heterogeneous leukemias.
    DOI:  https://doi.org/10.1126/scitranslmed.adr1471
  11. Blood Adv. 2025 May 07. pii: bloodadvances.2025015860. [Epub ahead of print]
    ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis.
    David M Ross, Florian H Heidel, Andrew C Perkins, Andreas Reiter, Carl Claudius Crodel, Caroline Hasselbalch Riley, María Teresa Gómez Casares, Istvan Takacs, Heiko Becker, Thomas Lehmann, Olga Yu Vinogradova, Kate Burbury, Alessandro M Vannucchi, Vikas Gupta, Marielle J Wondergem, Jean-Jacques Kiladjian, Grace Cleary, Angela Zhang, Jagannath Kota, Anirudh Cadapa Prahallad, Monika Wroclawska, Min Lu, Claire N Harrison.
      Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ~70% of patients discontinue ruxolitinib after ~5 years, a third of whom report suboptimal splenic response. ADORE was a Phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib+siremadlin (N=23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1-5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib+siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at Week 24 were observed, notably in several patients with SVR. An increase in GDF-15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015860
  12. Nat Commun. 2025 May 06. 16(1): 4214
    m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
    Feng Huang, Yushuai Wang, Xiuxin Zhang, Weiwei Gao, Jingwen Li, Ying Yang, Hongjie Mo, Emily Prince, Yifei Long, Jiacheng Hu, Chuang Jiang, Yalin Kang, Zhenhua Chen, Yueh-Chiang Hu, Chengwu Zeng, Lu Yang, Chun-Wei Chen, Jianjun Chen, Huilin Huang, Hengyou Weng.
      Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-58966-1
  13. EJHaem. 2025 Jun;6(3): e70049
    Outcomes With Venetoclax 50 mg, Hypomethylating Agents, and Voriconazole or Posaconazole in Acute Myeloid Leukemia.
    Kendall Diebold, Devan Parker, Sarah Worth, Manuel Espinoza-Gutarra, Pankit Vachhani, Kimo Bachiashvili, Sravanti Rangaraju, Razan Mohty, Ravi Bhatia, Omer Jamy.
       Background: Real-world evidence for hypomethylating agent (HMA) + venetoclax 50 mg (VEN50) with voriconazole and posaconazole in acute myeloid leukemia (AML), is limited.
    Methods: We evaluated outcomes of patients with newly-diagnosed AML treated with HMA + VEN50 with either posaconazole (n = 23) or voriconazole (n = 95).
    Results: We report that treatment with HMA + VEN50 with either azole elicits a response rate similar to that described in the VIALE-A trial. Reducing the VEN dose to 50 mg with either strong CYP3A4 inhibitor did not compromise on the efficacy of the combination.
    Conclusion: HMA + VEN50 with either posaconazole or voriconazole yields comparable responses to higher doses of VEN reported previously.
    Clinical trial registration: The authors have confirmed clinical trial registration is not needed for this submission.
    Keywords:  Venetoclax 50 mg; acute myeloid leukemia (AML); posaconazole; voriconazole
    DOI:  https://doi.org/10.1002/jha2.70049
  14. Br J Haematol. 2025 May 06.
    Ciclosporin A potentiates venetoclax efficacy in FLT3-ITD AML by targeting the NFATC1-AKT-mTOR-BCL-2/MCL-1 signaling axis.
    Yu Luo, Yinghao Fu, Mei Kuang, Jianming Wang, Runlong Zhao, Siqi Luo, Li Wang, Jieping Chen, Shuangnian Xu, Chengfang Zhou.
      The Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukaemia (AML) is associated with adverse clinical outcomes, including poor prognosis, high relapse rates and reduced responses to conventional treatment regimens. While venetoclax (VEN) monotherapy has shown limited efficacy in FLT3-ITD AML due to intrinsic resistance mechanisms, this study demonstrates that ciclosporin A (CsA) synergistically enhances VEN's anti-leukaemic activity. CsA significantly suppresses cell proliferation, induces mitochondrial apoptosis and impairs mitochondrial bioenergetics in FLT3-ITD AML cells. Mechanistically, CsA enhances the effects of VEN through the downregulation of NFATC1, a critical regulator of the PI3K/AKT/mTOR signalling pathway. This suppression of NFATC1 leads to the coordinated downregulation of the anti-apoptotic proteins BCL-2 and MCL-1, thereby overcoming resistance and reinstating therapeutic susceptibility in FLT3-ITD AML.
    Keywords:  FLT3‐ITD AML; NFATC1; PI3K/AKT/mTOR; ciclosporin A; venetoclax
    DOI:  https://doi.org/10.1111/bjh.20137
  15. Acta Haematol. 2025 May 05. 1-25
    Dose reduced induction therapy (A)-AIDA in patients with AML, being unfit for standard 7+3 chemotherapy and Literature Review of AML treatment in unfit/older AML patients.
    Karin Mayer, Leonie Birk, Katjana Schwab, Ingo G H Schmidt-Wolf, Marie von Lilienfeld-Toal, Peter Brossart, Axel Glasmacher, Corinna Hahn-Ast.
       INTRODUCTION: The standard induction chemotherapy in newly diagnosed acute myeloid leukemia (AML) is 7 days cytarabine and 3 days daunorubicin. However older and frail patients cannot be treated intensively. Before hypomethylating agents (HMA) plus venetoclax (VEN) was established we formulated a more tolerable induction therapy for these patients using continuous infusions of reduced doses of cytarabine (A) and idarubicin (IDA) in combination with ATRA (A), the (A)-AIDA regimen and trying to reach noteworthy and relevant remission rates with acceptable toxicities in this special population.
    METHODS: Between 1998 and 2015 older/frail patients with newly diagnosed or relapsed AML received (A)-AIDA. Treatment consisted of cytarabine 100mg/m2/d d1-5 and idarubicin 5mg/m2/d d1-5 as continuous infusion. Since 2003 ATRA (45 mg/m²/d d4-6, 15 mg/m²/d d7-28) was added in some patients.
    RESULTS: 154 patients received (A)-AIDA, median age was 71 years. In 40% the AML was secondary, 15.6% had relapsed AML. The complete remission rate was 41%, 7% reached a partial remission, the median overall survival was7 months. No significant differences of remission rates regarding various known risk factors for outcome with (A)-AIDA were detected.
    CONLUSION: Recent studies established HMA/venetoclax as first-line treatment for older/frail AML patients. Because (A)-AIDA is equally effective in patients with secondary or relapsed AML or ECOG>1, this regimen is an interesting treatment option for patients uneligible to HMA/venetoclax regimens.
    DOI:  https://doi.org/10.1159/000545792
  16. Blood Adv. 2025 May 07. pii: bloodadvances.2025016042. [Epub ahead of print]
    Asciminib remained superior vs bosutinib in late-line CML-CP after nearly 4 years of follow-up in ASCEMBL.
    Michael J Mauro, Yosuke Minami, Andreas Hochhaus, Elza Lomaia, Sergey Voloshin, Anna Turkina, Dong-Wook Kim, Jane F Apperley, Jorge Cortes, Andre Abdo, Laura Maria Fogliato, Dennis Dong Hwan Kim, Philipp le Coutre, Susanne Saussele, Mario Annunziata, Timothy P Hughes, Naeem Chaudhri, Lynette Chee, Valentin Garcia-Gutierrez, Koji Sasaki, Carla Boquimpani, Shruti Kapoor, Noemi Espurz-Abad, Vishal Dhamal, Delphine Rea.
      The efficacy of and disease control afforded by tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia in chronic phase (CML-CP) has led to increased longevity and thus continued pursuit of alternative therapies that are efficacious and maximize tolerability. The 24- and 96-week analyses from ASCEMBL demonstrated superior efficacy, safety, and tolerability of asciminib compared with bosutinib in later-line therapy, meeting primary and key secondary objectives, respectively. With nearly 4 years of follow-up, data from ASCEMBL continued to demonstrate superior efficacy, better safety, and greater tolerability of asciminib compared with bosutinib. At week 156, the major molecular response (MMR) rates remained higher with asciminib (33.8%) than bosutinib (10.5%); the difference in MMR rates between arms, after adjusting for baseline major cytogenetic response, was 23.2% (95% CI, 13.14%-33.18%; 2-sided P<0.001). Asciminib continued to cause fewer grade ≥3 adverse events (AEs) (59.6% vs 68.4%) and AEs leading to treatment discontinuation (8.3% vs 27.6%) than bosutinib. This updated analysis also includes patients who switched to asciminib due to lack of efficacy with bosutinib. Two of 25 patients who switched achieved MMR by the end of study, suggesting that earlier incorporation of asciminib, before other TKIs, may improve responses, albeit modestly. These long-term results further solidify asciminib as the therapy of choice for patients with CML-CP previously treated with ≥2 prior TKIs. This trial was registered at ClinicalTrials.gov as NCT03106779.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016042
  17. medRxiv. 2025 Apr 19. pii: 2025.04.15.25325668. [Epub ahead of print]
    Analysis of the effects of statin therapy on clonal dynamics in clonal haematopoiesis of indeterminate potential: insights from the English Longitudinal Study of Ageing.
    Ellen Nuttall Musson, Yvette Hoade, Phoebe Dace, Javier Herrero, Spiros Denaxas, Andrew Steptoe, Elspeth Payne.
      Clonal haematopoiesis of indeterminate potential (CHIP) is the acquisition of somatic mutations in leukaemia-associated genes in haematopoietic progenitors with age. It increases the risk of haematological malignancy (HM), cardiovascular disease (CVD) and mortality mediated by CHIP-associated inflammation, with larger clones posing higher risks. Statins have been found to reduce the risk of progression from myelodysplastic syndrome to acute myeloid leukaemia and have also shown efficacy in vitro against TET2 deficient AML cell lines. However, their effect on CHIP has not been described. This study characterises the English Longitudinal Study of Ageing as a novel longitudinal CHIP cohort, through genetic analysis of 13270 longitudinal peripheral blood samples from participants aged over 50. Using logistic and robust regression analysis, we show that statin therapy is associated with reduced TET2 CHIP clonal expansion in a gene specific manner. We also find that statin primary prevention is associated with significantly lower incidence of myocardial infarction and stroke in individuals with CHIP compared to controls. These findings provide evidence that a commonly prescribed mediation with a well characterised safety profile may modify the natural history of TET2 CHIP, thereby mitigating its associated health risks.
    DOI:  https://doi.org/10.1101/2025.04.15.25325668
  18. Leukemia. 2025 May 07.
    Myelodysplastic neoplasms with ring sideroblasts without SF3B1 mutations in adults: enrichment of germline variants in congenital sideroblastic anemia genes.
    Sandra Novoa-Jáuregui, Sandra Huber, Maria Gabarrós-Subirà, Tzu Hua Chen-Liang, Sara Torres-Esquius, Salvador Carrillo-Tornel, Marta Santiago, Teresa Bernal Del Castillo, Iván Martín-Castillo, Francisca Maria Hernandez, Mónica Del Rey, Alessandro Liquori, Mar Tormo, Jose Cervera, Francesc Bosch, David Valcárcel, Claudia Haferlach, María Díez-Campelo, María Julia Montoro, Torsten Haferlach, Andrés Jerez.
      
    DOI:  https://doi.org/10.1038/s41375-025-02629-z
  19. J Clin Invest. 2025 May 08. pii: e181394. [Epub ahead of print]
    PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via p53-mediated degradation.
    Pan Wang, Xu Han, Kehan Ren, Ermin Li, Honghao Bi, Inci Aydemir, Madina Sukhanova, Yijie Liu, Jing Yang, Peng Ji.
      The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). Pleckstrin-2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we revealed peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in MPN patients and a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2 mutated erythroid and myeloid proliferation in an induced pluripotent stem cell-derived human bone marrow organoid model. Our findings revealed PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negatively regulating p53, thus providing a target and an opportunity for drug repurposing by using cyclosporin A to treat MPNs.
    Keywords:  Bone marrow; Cancer; Cell biology; Hematology
    DOI:  https://doi.org/10.1172/JCI181394
  20. Curr Hematol Malig Rep. 2025 May 03. 20(1): 7
    Emerging Therapeutic Approaches for Anemia in Myelofibrosis.
    Helen T Chifotides, Andrea Duminuco, Elena Torre, Calogero Vetro, Patrick Harrington, Giuseppe A Palumbo, Prithviraj Bose.
       PURPOSE OF REVIEW: In this review, we highlight conventional agents and novel emerging therapeutic strategies to treat anemia in MF.
    RECENT FINDINGS: Anemia is a common and challenging feature of myelofibrosis (MF). The pathobiology of anemia is multifactorial, including progressive bone marrow fibrosis, decreased erythropoiesis due to high hepcidin levels leading to iron sequestration in the reticuloendothelial system, hypersplenism, erythropoiesis inhibition by myelosuppressive JAK inhibitors (ruxolitinib, fedratinib), and others. MF-associated anemia has a negative impact on survival. Conventional agents to manage anemia include erythropoiesis-stimulating agents, danazol, corticosteroids, and immunomodulatory agents, but responses are infrequent and lack durability. Notable advancements have emerged in developing novel treatments for anemia in MF, including the regulatory approval of momelotinib (ACVR1/JAK1/2 inhibitor) in 2023 and development of novel promising agents targeting hemojuvelin and activins. Momelotinib and pacritinib (ACVR1/JAK2 inhibitor) are the preferred JAK inhibitors for patients with cytopenias (anemia, thrombocytopenia). Luspatercept and elritercept are activin receptor ligand traps, promoting erythroid maturation and late-stage erythropoiesis. Currently, luspatercept is being evaluated in a phase 3 trial (INDEPENDENCE™) for anemia in MF patients who are on a JAK2 inhibitor and require transfusions, and in a phase 2 trial (ODYSSEY) in combination with momelotinib in MF patients who are transfusion dependent, whether or not on a JAK inhibitor. Interim results of the RESTORE trial demonstrated that elritercept significantly decreased transfusions in MF patients. DISC-0974 is a first-in-class anti-hemojuvelin (positive hepcidin regulator) monoclonal antibody that decreased hepcidin expression, increased serum iron, and enhanced erythropoiesis in anemic patients with MF in a phase 1b/2 study. Burgeoning studies of novel anemia-targeted agents and combinations are significantly improving the quality of life and outcomes of patients with MF. The recent approval of momelotinib to treat MF with anemia and the emerging novel anemia-directed strategies in early and advanced clinical development have ushered in a new era in the treatment of MF-related anemia.
    Keywords:  ACVR1 inhibitor; Anemia; Hepcidin; Luspatercept; Momelotinib; Myelofibrosis
    DOI:  https://doi.org/10.1007/s11899-025-00751-4
  21. Hemasphere. 2025 May;9(5): e70132
    Age-stratified machine learning identifies divergent prognostic significance of molecular alterations in AML.
    Jan-Niklas Eckardt, Waldemar Hahn, Rhonda E Ries, Szymon D Chrost, Susann Winter, Sebastian Stasik, Christoph Röllig, Uwe Platzbecker, Carsten Müller-Tidow, Hubert Serve, Claudia D Baldus, Christoph Schliemann, Kerstin Schäfer-Eckart, Maher Hanoun, Martin Kaufmann, Andreas Burchert, Johannes Schetelig, Martin Bornhäuser, Markus Wolfien, Soheil Meshinchi, Christian Thiede, Jan Moritz Middeke.
      Risk stratification in acute myeloid leukemia (AML) is driven by genetics, yet patient age substantially influences therapeutic decisions. To evaluate how age alters the prognostic impact of genetic mutations, we pooled data from 3062 pediatric and adult AML patients from multiple cohorts. Signaling pathway mutations dominated in younger patients, while mutations in epigenetic regulators, spliceosome genes, and TP53 alterations became more frequent with increasing age. Machine learning models were trained to identify prognostic variables and predict complete remission and 2-year overall survival, achieving area-under-the-curve scores of 0.801 and 0.791, respectively. Using Shapley (SHAP) values, we quantified the contribution of each variable to model decisions and traced their impact across six age groups: infants, children, adolescents/young adults, adults, seniors, and elderly. The highest contributions to model decisions among genetic variables were found for alterations of NPM1, CEBPA, inv(16), and t(8;21) conferring favorable risk and alterations of TP53, RUNX1, ASXL1, del(5q), -7, and -17 conferring adverse risk, while FLT3-ITD had an ambiguous role conferring favorable treatment responses yet poor overall survival. Age significantly modified the prognostic value of genetic alterations, with no single alteration consistently predicting outcomes across all age groups. Specific alterations associated with aging such as TP53, ASXL1, or del(5q) posed a disproportionately higher risk in younger patients. These results challenge uniform risk stratification models and highlight the need for context-sensitive AML treatment strategies.
    DOI:  https://doi.org/10.1002/hem3.70132
  22. Leukemia. 2025 May 08.
    Regulation of H3K4me3 breadth and MYC expression by the SETD1B catalytic domain in MLL-rearranged leukemia.
    Shintaro Izumi, Ko Ohtani, Makoto Matsumoto, Seito Shibata, Bahityar Rahmutulla, Masaki Fukuyo, Mitsutaka Nishimoto, Hideo Miyagawa, Emiko Sakaida, Koutaro Yokote, Issay Kitabayashi, Kimi Araki, Atsushi Kaneda, Takayuki Hoshii.
      Histone H3 lysine 4 trimethylation (H3K4me3) is abundant in mixed-lineage leukemia-rearranged (MLL-r) acute myeloid leukemia (AML) cells; however, the responsible enzymes and their roles remain unclear. This study aimed to identify the modifier responsible for high H3K4me3 modification in MLL-r leukemia and its downstream targets essential for the cell proliferation. Here, we performed a CRISPR-tiling screen against known H3K4 methylation modifiers in an MLL-r AML model. Disrupting the SETD1B catalytic SET domain caused depletion of FLT3-ITD or NrasG12D-expressing AML cells, and gene expression downregulation, particularly in the MYC pathway. SETD1B SET domain loss results in a significant decrease in H3K4me3 breadth. Exogenous MYC expression or disrupting H3K4 demethylase KDM5C significantly restored growth defects in SETD1B SET domain-mutant cells. These data indicated that SETD1B was required for H3K4me3 breadth and MYC expression. Thus, a thorough understanding of SETD1B-mediated H3K4me3 breadth is critical for developing markers and therapies for MYC-dependent leukemia subtypes.
    DOI:  https://doi.org/10.1038/s41375-025-02638-y
  23. Blood. 2025 May 07. pii: blood.2024027368. [Epub ahead of print]
    ANKRD26-related Thrombocytopenia 2 with a Baseline Increase in Blasts: Implications for Clinical Surveillance.
    Lara Wahlster, Lucy A Godley, Jason X Cheng, Michael W Drazer, Christopher R Reilly, Geraldine S Pinkus, Jared H Rowe, Nina Weichert-Leahey, Robert Grant Rowe, Lev Gorfinkel, Karyn Jean Brundige, Franziska Wachter, Luana Miria Messa, Alan D Michelson, Alan B Cantor, Akiko Shimamura, Jacob R Bledsoe.
      We report eight patients with ANKRD26-related thrombocytopenia-2 (ANKRD26-RT) with elevated bone marrow myeloblasts and dysmegakaryopoiesis, without somatic genetic abnormalities or progression to malignancy during long-term observation, findings which may constitute inherent ANKRD26-RT biology rather than progression to myeloid malignancy.
    DOI:  https://doi.org/10.1182/blood.2024027368
  24. Blood. 2025 May 07. pii: blood.2024026711. [Epub ahead of print]
    Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F- positive MPNs in vivo.
    Nicolas Papadopoulos, Audrey Nédélec, Yacine Rahmani, Hosuk Ryou, Jean-Philippe Defour, Jens Rittscher, Daniel Royston, Stefan N Constantinescu.
      The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling of several type I cytokine receptors, namely those for erythropoietin (EpoR), thrombopoietin (TpoR), and Granulocyte Colony Stimulating Factor (G-CSFR). Among these, TpoR assumes a pivotal role in hematopoietic stem cell renewal and differentiation, being positioned as a key driver of MPNs alongside mutated Jak2. However, the impact of TpoR/MPL absence in the context of Jak2 V617F in vivo has been explored only through a transgenic Jak2 V617F mouse model, where regulation of Jak2 expression does not depend on its natural promoter. In this study, we use a novel mouse model expressing Jak2 V617F under its endogenous promoter at the heterozygous state within a Mpl knock-out background. Our findings indicate that erythrocytosis, leukocytosis and moderate splenomegaly with mild spleen peri-vascular fibrosis persist even in the absence of Mpl expression. Notably, the inherent growth-stimulating effect induced by Jak2 V617F remains consistent across diverse early hematopoietic progenitor populations in the absence of Mpl but is reduced at the stem cell level and does not allow clonal expansion in competitive transplantation. Our results delineate Mpl-dependent and -independent phenotypes induced by Jak2 V617F and confirm that inhibiting Mpl expression at the stem cell level negates the long-term advantage of the mutant clone. Consequently, while MPL emerges as a major player in Jak2 V617F positive MPNs, our study underscores that it is not the exclusive contributor, broadening the spectrum for therapeutic intervention.
    DOI:  https://doi.org/10.1182/blood.2024026711
  25. Br J Haematol. 2025 May 02.
    How to use luspatercept and erythropoiesis-stimulating agents in low-risk myelodysplastic syndrome.
    Valeria Santini, Angela Consagra.
      Anaemia is the most common cytopenia in myelodysplastic syndrome (MDS), significantly impacting quality of life and morbidity. Erythropoiesis-stimulating agents (ESAs) are the first-line treatment for anaemia in lower risk (LR)-MDS. The European Medicines Agency (EMA) approved epoetin alpha for LR-MDS-related anaemia in 2017, based on evidence from a unique randomized Phase 3 trial and accumulated evidence in many trials, providing support to an already widely utilized therapeutic option. Luspatercept, a more recently approved agent, is a ligand trap for transforming growth factor beta (TGF-β) pathway, whose activation is associated with impaired terminal erythroid maturation in MDS. Luspatercept facilitates late-stage erythroid differentiation, improving transfusion-dependent anaemia in LR-MDS, and has shown activity after ESA failure in MDS-ring sideroblasts (RS) and in all subtypes of MDS ESA naïve transfusion-dependent patients. Due to the recent approval of luspatercept also in ESA naïve LR-MDS, it has become crucial to determine the optimal treatment algorithm for anaemic LR-MDS, before and after transfusion dependence. ESAs and luspatercept are characterized by distinct mechanisms of action, and their integration into treatment strategies is already possible, but requires further evidence to maximize efficacy and improve patient outcomes.
    Keywords:  ESAs; anaemia; erythropoietin; low‐risk myelodysplastic syndromes; luspatercept; transfusion dependence
    DOI:  https://doi.org/10.1111/bjh.20126
  26. Blood. 2025 May 07. pii: blood.2024028303. [Epub ahead of print]
    Phase 1/2 Study of High-Dose Palifermin for GVHD Prophylaxis in Patients Undergoing HLA-Matched Unrelated Donor HCT.
    Eduard Schulz, Lauren M Curtis, Noa G Holtzman, Jennifer Sponaugle, Kaska Wloka, Alen Ostojic, Alain Mina, Najla El Jurdi, Filip Pirsl, Ashley Carpenter, Mahshid Golagha, Arlene Sirajuddin, Theo Heller, Brian C Shaffer, Frances T Hakim, Jeffrey Steven Rubin, Ronald E Gress, Steven Z Pavletic.
      Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). Palifermin, a recombinant N-truncated keratinocyte growth factor (KGF), protects epithelial tissues, including the thymus and gut. While high-dose KGF prevents GVHD in preclinical models, lower doses of palifermin were ineffective in humans. We conducted a phase 1/2 trial evaluating high-dose palifermin for preventing severe chronic GVHD (GVHD) in matched unrelated donor T-cell replete peripheral-blood HCT following reduced-intensity conditioning (RIC). Using a 3+3 design, we determined the recommended phase 2 dose (RP2D), followed by an expansion phase. Palifermin (180-720 μg/kg) was given on day -7 before HCT. All 31 patients received fludarabine/cyclophosphamide RIC with tacrolimus, methotrexate, and sirolimus for GVHD prophylaxis. Palifermin was well tolerated, with self-limiting rash and pancreatic enzyme elevations as notable grade 3/4 adverse events. The RP2D was 720 μg/kg. Remarkably, no patients at this dose developed grade II-IV acute GVHD (0/19), though severe chronic GVHD rates (primary endpoint) remained unchanged compared to historical controls. Post-transplant lymphocyte phenotyping suggests palifermin modulates Treg and naïve CD4+ T-cell numbers. These findings indicate high-dose palifermin with RIC is safe and may prevent acute GVHD, though it did not impact chronic GVHD rates in this study. NCT02356159.
    DOI:  https://doi.org/10.1182/blood.2024028303
  27. Br J Haematol. 2025 May 08.
    Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations.
    Yvonne Lisa Behrens, Thea Reinkens, Winfried Hofmann, Amelie Gumann, Alisa Förster, Laura Gaschler, Tabita Ghete, Renate Strasser, Jennifer Espenkötter, Bernd Haermeyer, Michaela Losch, Stephanie Sembill, Zofia Wotschofsky, Stephan von Hörsten, Wolfgang Schuh, Nataliya Di Donato, Meinolf Suttorp, Manuela Krumbholz, Tim Ripperger, Brigitte Schlegelberger, Gudrun Göhring, Markus Metzler, Axel Karow.
      Paediatric blast-phase chronic myeloid leukaemia (CML-BP) is a rare and serious condition. Of 231 paediatric patients enrolled in the German CML-PAED-II registry between January 2007 and September 2023, 25 individuals (11%) were diagnosed with CML-BP. To identify genetic variants associated with early onset and disease transformation, we performed whole genome sequencing (WGS), deep targeted sequencing and cytogenetic analyses in 19 cases with de novo (n = 11) or secondary (n = 8) CML-BP and sufficient available biomaterial. Copy number variants (CNVs) were more frequent than single nucleotide variants (SNVs) and more prevalent in secondary than in de novo CML-BP. Recurrent pathogenic somatic SNVs were observed in ABL1 (n = 5, 24%), RUNX1 (n = 2, 12%) and ASXL1 (n = 2, 12%). Nine patients (47%) carried pathogenic germline (n = 8) or somatic (n = 1) variants in either of the genes ATM, CHEK2, FANCM, HERC2, NBN, RAD54B, RECQL4, SETD2 or TP63 belonging to the DNA damage response (DDR). Within a comparison cohort of 19 patients with chronic phase paediatric CML, only one individual (5%) exhibited a pathogenic DDR germline variant. Our study provides novel pathogenetic insights into paediatric CML-BP. The identification of pathogenic DDR-associated germline variants suggests a genetic predisposition with potential implications for patients and families concerning cancer treatment and surveillance.
    Keywords:  DNA damage repair; blast phase; molecular response; paediatric chronic myeloid leukaemia; somatic variant profile; whole genome sequencing
    DOI:  https://doi.org/10.1111/bjh.20133
  28. Cell Rep. 2025 May 07. pii: S2211-1247(25)00432-2. [Epub ahead of print]44(5): 115661
    The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.
    Songyu Li, Ya Liu, Xiang Wu, Minjia Pan, Hongxia Zhao, Yunguang Hong, Qinghua Zhang, Shushu Hu, Aorong Ouyang, Guangru Li, Minhui Wu, Shanshan Fan, Zhirong Jia, Shanchao Zhao, Guocai Wu, Xiangwei Gao, Zhigang Yang, Zhanghui Chen.
      Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m5C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m5C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m5C axis for the treatment of this cancer.
    Keywords:  5-methylcytosine; AML; Acute myeloid leukemia; CP: Cancer; CP: Metabolism; NOP2/Sun RNA methyltransferase 2; NSUN2; m(5)C; serine metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.115661
  29. Hemasphere. 2025 May;9(5): e70137
    Event-free survival in early polycythemia vera patients correlates with molecular response to ropeginterferon alfa-2b or hydroxyurea/best available therapy (PROUD-PV/CONTINUATION-PV).
    PROUD‐PV Study Group
      
    DOI:  https://doi.org/10.1002/hem3.70137
  30. Mol Ther. 2025 May 05. pii: S1525-0016(25)00361-2. [Epub ahead of print]
    Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.
    Syed Feroj Ahmed, Jayanthi Anand, Wei Zhang, Lori Buetow, Loveena Rishi, Louise Mitchell, Jonathan Bohlen, Sergio Lilla, Gary J Sibbet, Colin Nixon, Amrita Patel, Karolina A Majorek, Sara Zanivan, Jacinta C Bustamante, Sachdev S Sidhu, Karen Blyth, Danny T Huang.
      Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase critical for negatively regulating receptor protein tyrosine kinases (RTKs). Deleterious CBL mutants lose E3 activity, but act as adaptors that gain function to cause myeloproliferative neoplasms. Currently, there is no targeted treatment available for patients with CBL mutant-dependent disorders. By combining phage-display technology and structure-based optimization, we discovered CBLock, a nanomolar affinity peptide inhibitor, that binds the substrate-binding site of CBL's tyrosine kinase binding domain (TKBD). CBLock disrupts the interaction between CBL mutants and RTKs, thereby impairing RTK-mediated priming of adaptor function of CBL mutants and downstream signaling. Notably, CBLock binds TKBD without inducing conformational changes, thereby preserving its ligand-free native conformation. In contrast, when CBL binds RTK substrates, TKBD undergoes a conformational change. Maintaining the native CBL TKBD conformation was crucial for CBLock to inhibit proliferation, induce cell cycle arrest, and promote apoptosis in leukemia cells harboring CBL mutations. In a mouse xenograft model of acute myeloid leukemia (AML), CBLock reduced tumor burden and improved survival rate. Moreover, CBLock inhibited the proliferation of cells derived from patients with CBL mutations. Therefore, inhibiting CBL TKBD in its native state presents a promising therapeutic opportunity in targeting mutant CBL-dependent leukemia.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.04.042
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