bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–06–02
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells.
  2. RUNX1::ETO and CBFβ::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core-binding factor-acute myeloid leukaemia.
  3. Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.
  4. Prognostic impact of 'multi-hit' versus 'single hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.
  5. Lower intensity therapy with cladribine/low dose cytarabine/venetoclax in older patients with acute myeloid leukemia compares favorably with intensive chemotherapy among patients undergoing allogeneic stem cell transplantation.
  6. Evaluation of European LeukemiaNet 2022 risk classification in patients undergoing allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: Identification of a very poor prognosis genetic group.
  7. CHIPing away at proteomics to find correlations with myeloid neoplasms.
  8. Results of ponatinib as frontline therapy for chronic myeloid leukemia in chronic phase.
  9. Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia.
  10. Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of cell cycle.
  11. Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.
  12. Parallel genomic analysis from paired bone marrow and peripheral blood samples of 200 cytopenic patients.
  13. TP53 mutation screening for patients at risk of myeloid malignancy.
  14. Lower relapse incidence with HAPLO versus MSD or MUD HCTs for AML patients with KMT2A rearrangement: a study from the Global Committee and the ALWP of the EBMT.
  15. In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia.
  16. Novel somatic mutations in blood driving age-related clonal hematopoiesis.
  17. Targeting CD38 by isatuximab and a CD38/CD3xCD28 trispecific T-cell engager in old patients with acute myeloid leukemia.
  18. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.
  19. BRD9 regulates normal human hematopoietic stem cell function and lineage differentiation.
  20. EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion.
  21. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis.
  22. Air Pollutant Impact on Disease Characteristics and Outcomes in Patients with Acute Myeloid Leukemia.
  23. Enhancing prime editing in hematopoietic stem and progenitor cells by modulating nucleotide metabolism.
  24. PARP inhibition leads to synthetic lethality with key splicing-factor mutations in myelodysplastic syndromes.
  25. Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes.
  26. Metabolic adaptation pilots the differentiation of human hematopoietic cells.
  27. Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells.
  28. Molecular prognostication for transplant decision making of patients with myelodysplastic syndromes: A retrospective single-center study.
  29. Donor lymphocyte infusion after allogeneic haematopoietic cell transplantation for haematological malignancies: basic considerations and best practice recommendations from the EBMT.
  30. Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells.
  31. Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia.
  1. Cancer Discov. 2024 May 31.
    CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells.
    Michael R Waarts, Shoron Mowla, Meaghan Boileau, Anthony R Martinez Benitez, Junya Sango, Maya Bagish, Ines Fernandez-Maestre, Yufan Shan, Shira E Eisman, Young C Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C Romero-Vega, Linde A Miles, Wenbin Xiao, Xiaodi Wu, Richard P Koche, Scott A Armstrong, Alan H Shih, Eirini P Papapetrou, Jason M Butler, Sheng F Cai, Robert L Bowman, Ross L Levine.
      Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1092
  2. Br J Haematol. 2024 May 27.
    RUNX1::ETO and CBFβ::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core-binding factor-acute myeloid leukaemia.
    Siyang Wang, Yabin Liu, Xujie Zhao, Xiaoling Wang, Jiacheng Lou, Peng Jin, Yi Zhang, Jinyi Yu, Kankan Wang.
      Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFβ::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFβ::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.
    Keywords:  BCAT1; CBFβ::MYH11; RUNX1::ETO; core‐binding factor‐acute myeloid leukaemia
    DOI:  https://doi.org/10.1111/bjh.19565
  3. Leukemia. 2024 May 29.
    Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.
    Ruiqi Zhu, Courtney M Shirley, S Haihua Chu, Li Li, Bao H Nguyen, Jaesung Seo, Min Wu, Tessa Seale, Amy S Duffield, Louis M Staudt, Mark Levis, Yu Hu, Donald Small.
      Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or γ-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cells in vitro. NOTCH4 inhibition sensitized TKI-resistant FLT3/ITD cells to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed that the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML with FLT3/ITD mutations.
    DOI:  https://doi.org/10.1038/s41375-024-02292-w
  4. Haematologica. 2024 May 30.
    Prognostic impact of 'multi-hit' versus 'single hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.
    Talha Badar, Ahmad Nanaa, Ehab Atallah, Rory M Shallis, Emily C Craver, Zhuo Li, Aaron D Goldberg, Antoine N Saliba, Anand Patel, Jan P Bewersdorf, Adam Duvall, Madelyn Burkart, Danielle Bradshaw, Yasmin Abaza, Maximilian Stahl, Neil Palmisiano, Guru Subramanian Guru Murthy, Amer M Zeidan, Vamsi Kota, Mrinal M Patnaik, Mark R Litzow.
      While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.
    DOI:  https://doi.org/10.3324/haematol.2024.285000
  5. Cancer. 2024 May 29.
    Lower intensity therapy with cladribine/low dose cytarabine/venetoclax in older patients with acute myeloid leukemia compares favorably with intensive chemotherapy among patients undergoing allogeneic stem cell transplantation.
    Jayastu Senapati, Hagop M Kantarjian, Alexandre Bazinet, Patrick Reville, Nicholas J Short, Naval Daver, Gautam Borthakur, Alex Bataller, Elias Jabbour, Courtney DiNardo, Fadi Haddad, Koji Sasaki, Uday Popat, Betul Oran, Amin M Alousi, Sanam Loghavi, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia.
       BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes.
    METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation.
    RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486).
    CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.
    Keywords:  AML; cladribine; older patients; stem cell transplantation; venetoclax
    DOI:  https://doi.org/10.1002/cncr.35388
  6. Br J Haematol. 2024 May 29.
    Evaluation of European LeukemiaNet 2022 risk classification in patients undergoing allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: Identification of a very poor prognosis genetic group.
    Carlos Jiménez-Vicente, Paola Charry, Sandra Castaño-Diez, Francesca Guijarro, Mònica López-Guerra, Amanda Isabel Pérez-Valencia, Alexandra Martinez-Roca, Albert Cortés-Bullich, Daniel Munárriz, Maria Teresa Solano, Laura Rosiñol, Enric Carreras, Álvaro Urbano-Ispizua, Francesc Fernández-Avilés, Carmen Martinez, María Suárez-Lledó, Marina Díaz-Beyá, Montserrat Rovira, María Queralt Salas, Jordi Esteve.
      European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia-free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse-plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2-year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo-HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group.
    Keywords:  HSC transplantation; acute leukaemia; classifications; clinical cytogenetics
    DOI:  https://doi.org/10.1111/bjh.19518
  7. Clin Cancer Res. 2024 May 31.
    CHIPing away at proteomics to find correlations with myeloid neoplasms.
    Avni M Bhalgat, Justin Taylor.
      Plasma proteomic profiling to identify associations with myeloid neoplasm (MN) risk, highlights the potential of integrating protein and genetic biomarkers for detection individuals at high-risk of developing MN. These proteins also offer valuable insights into biological pathways and inflammatory mechanisms involved in the progression of clonal hematopoiesis (CH) to MN.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-0827
  8. Cancer. 2024 May 28.
    Results of ponatinib as frontline therapy for chronic myeloid leukemia in chronic phase.
    Fadi G Haddad, Koji Sasaki, Lewis Nasr, Nicholas J Short, Tapan Kadia, Sara Dellasala, Jorge Cortes, Franck E Nicolini, Ghayas C Issa, Elias Jabbour, Hagop Kantarjian.
       BACKGROUND: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase.
    METHODS: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI.
    RESULTS: Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%).
    CONCLUSION: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.
    Keywords:  T315I mutation; cardiovascular; first line; third‐generation; toxicity; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1002/cncr.35384
  9. bioRxiv. 2024 May 14. pii: 2024.05.11.593633. [Epub ahead of print]
    Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia.
    Benjamin J Rodems, Sonali Sharma, Cameron D Baker, Christina M Kaszuba, Takashi Ito, Jane L Liesveld, Laura M Calvi, Michael W Becker, Craig T Jordan, John M Ashton, Jeevisha Bajaj.
      Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified 1-6 , concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR based in vivo LSC dependency map 7 to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemias in vivo by downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax 8, 9 to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.
    DOI:  https://doi.org/10.1101/2024.05.11.593633
  10. Blood. 2024 May 28. pii: blood.2023021426. [Epub ahead of print]
    Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of cell cycle.
    Carys S Johnson, Matthew J Williams, Kendig Sham, Serena Belluschi, Wenjuan Ma, Xiaonan Wang, Winnie Wy Lau, Kerstin Kaufmann, Gabriela Krivdova, Emily Francesca Calderbank, Nicole Mende, Jessica McLeod, Giovanna Mantica, Juan Li, Charlotte Grey-Wilson, Michael Drakopoulos, Shaaezmeen Basheer, Shubhankar Sinha, Evangelia Diamanti, Christina Basford, Nicola K Wilson, Steven J Howe, John E Dick, Berthold Gottgens, Anthony R Green, Natalie Francis, Elisa Laurenti.
      Loss of long-term hematopoietic stem cell (LT-HSC) function ex vivo hampers the success of clinical protocols reliant on culture. However, the kinetics and mechanisms by which this occurs remain incompletely characterized. Here, through time-resolved scRNA-Seq, matched in vivo functional analysis and the use of a reversible in vitro system of early G1 arrest, we define the sequence of transcriptional and functional events occurring during the first ex vivo division of human LT-HSCs. We demonstrate that the sharpest loss of LT-HSC repopulation capacity happens early on, between 6 and 24 hours of culture, before LT-HSCs commit to cell cycle progression. During this time window, LT-HSCs adapt to the culture environment, limiting global variability in gene expression and transiently upregulating gene networks involved in signaling and stress responses. From 24 hours, LT-HSC progression past early G1 contributes to the establishment of differentiation programmes in culture. However, contrary to current assumptions, we demonstrate that loss of HSC function ex vivo is independent of cell cycle progression. Finally, we show that targeting LT-HSC adaptation to culture by inhibiting early activation of JAK/STAT signaling improves HSC long-term repopulating function ex vivo. Collectively, our study demonstrates that controlling early LT-HSC adaptation to ex vivo culture, for example via JAK inhibition, is of critical importance to improve HSC gene therapy and expansion protocols.
    DOI:  https://doi.org/10.1182/blood.2023021426
  11. Nat Cancer. 2024 May 30.
    Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.
    Lois M Kelly, Justine C Rutter, Kevin H Lin, Frank Ling, Matthieu Duchmann, Emmanuelle Latour, Nadia Arang, Hélène Pasquer, Duong Ho Nhat, Juliette Charles, Shane T Killarney, Hazel X Ang, Federica Namor, Cécile Culeux, Bérangère Lombard, Damarys Loew, Danielle L Swaney, Nevan J Krogan, Luc Brunel, Élodie Carretero, Pascal Verdié, Muriel Amblard, Sofiane Fodil, Tony Huynh, Marie Sebert, Lionel Adès, Emmanuel Raffoux, Nina Fenouille, Raphaël Itzykson, Camille Lobry, Lina Benajiba, Antoine Forget, Anthony R Martin, Kris C Wood, Alexandre Puissant.
      Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.
    DOI:  https://doi.org/10.1038/s43018-024-00782-5
  12. Leukemia. 2024 May 28.
    Parallel genomic analysis from paired bone marrow and peripheral blood samples of 200 cytopenic patients.
    Sandra Huber, Natalie Wossidlo, Torsten Haferlach, Stephan Hutter, Wencke Walter, Christian Pohlkamp, Isolde Summerer, Henning Ruge, Constance Baer, Gregor Hoermann, Manja Meggendorfer, Wolfgang Kern, Claudia Haferlach.
      
    DOI:  https://doi.org/10.1038/s41375-024-02297-5
  13. Leukemia. 2024 May 25.
    TP53 mutation screening for patients at risk of myeloid malignancy.
    Devdeep Mukherjee, Rialnat A Lawal, Courtney D Fitzhugh, Christopher S Hourigan, Laura W Dillon.
      
    DOI:  https://doi.org/10.1038/s41375-024-02283-x
  14. Blood Cancer J. 2024 May 27. 14(1): 85
    Lower relapse incidence with HAPLO versus MSD or MUD HCTs for AML patients with KMT2A rearrangement: a study from the Global Committee and the ALWP of the EBMT.
    Yishan Ye, Myriam Labopin, Jia Chen, Depei Wu, Tobias Gedde-Dahl, Didier Blaise, Gérard Socie, Edouard Forcade, Urpu Salmenniemi, Sébastien Maury, Jurjen Versluis, Ali Bazarbachi, Arnon Nagler, Eolia Brissot, Lin Li, Yi Luo, Jimin Shi, Fabio Ciceri, He Huang, Mohamad Mohty, Norbert Claude Gorin.
      
    DOI:  https://doi.org/10.1038/s41408-024-01072-0
  15. bioRxiv. 2024 May 18. pii: 2024.05.16.594555. [Epub ahead of print]
    In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia.
    Bill H Chang, Karina Thiel-Klare, Jeffrey W Tyner.
      PTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid Leukemia (AML), and Acute Lymphoblastic Leukemia (ALL). Since activating mutations of PTPN11 increase proliferative signaling and cell survival through the RAS/MAPK proliferative pathway there is significant interest in using MEK inhibitors for clinical benefit. Yet, single agent clinical activity has been minimal. Previously, we showed that PTPN11 is further activated by upstream tyrosine kinases TNK2/SRC, and that PTPN11-mutant JMML and AML cells are sensitive to TNK2 inhibition using dasatinib. In these studies, we adopted a genetically engineered mouse model of PTPN11 driven leukemia using the mouse strain 129S/Sv- Ptpn11 tm6Bgn /Mmucd crossed with B6.129P2- Lyz2 tm1(cre)Ifo /J. The F1 progeny expressing Ptpn11 D61Y within hematopoietic cells destined along the granulocyte-monocyte progenitor lineage developed a myeloproliferative disorder. Cohorts of animals treated with combination of dasatinib and trametinib had a significant effect in mitigating disease parameters compared to single agents. Further, a primary patient-derived xenograft model using a myeloid leukemia with PTPN11 F71L also displayed improved response to combination. Collectively, these studies point to combined therapies targeting MEK and TNK2/SRC as a promising therapeutic potential for PTPN11-mutant leukemias.
    Key Points: Combining MEK and TNK2/SRC inhibitors has therapeutic potential in PTPN11 mutant JMML and AML.
    DOI:  https://doi.org/10.1101/2024.05.16.594555
  16. Nat Genet. 2024 May 28.
    Novel somatic mutations in blood driving age-related clonal hematopoiesis.
      
    DOI:  https://doi.org/10.1038/s41588-024-01756-0
  17. Blood Adv. 2024 May 30. pii: bloodadvances.2024013212. [Epub ahead of print]
    Targeting CD38 by isatuximab and a CD38/CD3xCD28 trispecific T-cell engager in old patients with acute myeloid leukemia.
    Esperanza Martin-Sanchez, Laura Blanco Fernández, Peter S Kim, Kamlesh Bisht, Hongfang Wang, Helgi Van de Velde, Tomas Jelinek, Catia Simoes, Felipe Prosper, Jesús F San-Miguel, Ana Alfonso, Juan Miguel Bergua Burgues, Rebeca Rodríguez-Veiga, Susana Vives, David Martínez-Cuadrón, Pau Montesinos, Bruno Paiva, Aintzane Zabaleta.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013212
  18. N Engl J Med. 2024 May 31.
    Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.
    ASC4FIRST Investigators
       BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).
    METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.
    RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).
    CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).
    DOI:  https://doi.org/10.1056/NEJMoa2400858
  19. Cell Death Differ. 2024 May 30.
    BRD9 regulates normal human hematopoietic stem cell function and lineage differentiation.
    Swati Garg, Wei Ni, Basudev Chowdhury, Ellen L Weisberg, Martin Sattler, James D Griffin.
      Bromodomain containing protein 9 (BRD9), a member of the non-canonical BRG1/BRM-associated factor (ncBAF) chromatin remodeling complex, has been implicated as a synthetic lethal target in AML but its function in normal human hematopoiesis is unknown. In hematopoietic stem and progenitor cells (HSPC) genomic or chemical inhibition of BRD9 led to a proliferative disadvantage and loss of stem cells in vitro. Human HSPCs with reduced BRD9 protein levels produced lower numbers of immature mixed multipotent GEMM colonies in semi-solid media. In lineage-promoting culture conditions, cells with reduced BRD9 levels failed to differentiate into the megakaryocytic lineage and showed delayed differentiation into erythroid cells but enhanced terminal myeloid differentiation. HSPCs with BRD9 knock down (KD) had reduced long-term multilineage engraftment in a xenotransplantation assay. An increased number of downregulated genes in RNAseq analysis after BRD9 KD coupled with a gain in chromatin accessibility at the promoters of several repressive transcription factors (TF) suggest that BRD9 functions in the maintenance of active transcription during HSC differentiation. In particular, the hematopoietic master regulator GATA1 was identified as one of the core TFs regulating the gene networks modulated by BRD9 loss in HSPCs. BRD9 inhibition reduced a GATA1-luciferase reporter signal, further suggesting a role for BRD9 in regulating GATA1 activity. BRD9 is therefore an additional example of epigenetic regulation of human hematopoiesis.
    DOI:  https://doi.org/10.1038/s41418-024-01306-5
  20. bioRxiv. 2024 May 17. pii: 2024.05.14.594150. [Epub ahead of print]
    EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion.
    Nathaniel J Buteyn, Connor G Burke, Vincent J Sartori, Eve Deering-Gardner, Zachary J DeBruine, Dahlya Kamarudin, Darrell P Chandler, Alexander C Monovich, Monika W Perez, Joanna S Yi, Rhonda E Ries, Todd A Alonzo, Russell Jh Ryan, Soheil Meshinchi, Timothy J Triche.
      Minimal improvement in outcomes for high-risk pediatric acute myeloid leukemia (pAML) patients has been made in the past decades. Nowhere is this more evident than in patients carrying a t(16;21)(p11;q22) FUS::ERG translocation; quick time to relapse and universal failure of hematopoietic stem cell transplant contribute to one of the lowest survival rates in childhood leukemia. Here, we have identified a unique, defining immune-evasion phenotype in FUS::ERG pAML driven by EZH2 and characterized by loss of MHC class I and II molecules and immune co-stimulatory receptors. This loss of immune engagement, present at diagnosis, allows pervasiveness of blasts that prove resistant to standard treatment. We demonstrate that treatment with the FDA-approved EZH2 inhibitor tazemetostat, in combination with IFN-γ, reverses the phenotype, re-expresses MHC receptor expression, and reduces blast viability. EZH2 inhibitors provide a novel therapeutic option for this high-risk population and may prove a beneficial supplemental treatment for FUS::ERG pAML.
    STATEMENT OF SIGNIFICANCE: FUS::ERG pAML patients have dismal outcomes. Here we show a ubiquitous immune-evasive phenotype, defined by elevated EZH2 levels and loss of MHC class I and II receptors, is present in these patients at diagnosis. Treatment with the EZH2 inhibitor Tazemetostat successfully reverses the phenotype in a patient-derived cell line model.
    DOI:  https://doi.org/10.1101/2024.05.14.594150
  21. Blood Adv. 2024 May 31. pii: bloodadvances.2024012939. [Epub ahead of print]
    Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis.
    Aaron T Gerds, Claire N Harrison, Jean-Jacques Kiladjian, Ruben Mesa, Alessandro Maria Vannucchi, Rami S Komrokji, Prithviraj Bose, Marina Kremyanskaya, Adam Mead, Jason Gotlib, Shelonitda Rose, Fabian Sanabria, Niloufar Marsousi, Ana Carolina Giuseppi, Huijing Jiang, Jeanne M Palmer, Kelly McCaul, Vincent Ribrag, Francesco Passamonti.
      The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin increase ≥1.5 g/dL from baseline. Among TD patients, ~50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. NCT03194542 clinicaltrials.gov.
    DOI:  https://doi.org/10.1182/bloodadvances.2024012939
  22. Blood Adv. 2024 May 29. pii: bloodadvances.2024013280. [Epub ahead of print]
    Air Pollutant Impact on Disease Characteristics and Outcomes in Patients with Acute Myeloid Leukemia.
    Andrew Stephen Palmer, Garth H Rauscher, Ivy Elizabeth Abraham, Madelyn Burkart, Ami Dave, Nepheli Ioanna Raptis, Ahmed Aleem, Vedavyas Gannamani, Amani Erra, Sarah Monick, Carlos Galvez, Syed Abdul Mannan Shah, Hamed Rahmani Youshanlouei, Melissa L Larson, Maryam Zia, Stephanie B Tsai, Jessica K Altman, Wendy Stock, Irum Khan, Anand A Patel.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013280
  23. Nat Biotechnol. 2024 May 28.
    Enhancing prime editing in hematopoietic stem and progenitor cells by modulating nucleotide metabolism.
    Sébastien Levesque, Andrea Cosentino, Archana Verma, Pietro Genovese, Daniel E Bauer.
      Therapeutic prime editing of hematopoietic stem and progenitor cells (HSPCs) holds great potential to remedy blood disorders. Quiescent cells have low nucleotide levels and resist retroviral infection, and it is possible that nucleotide metabolism could limit reverse transcription-mediated prime editing in HSPCs. We demonstrate that deoxynucleoside supplementation and Vpx-mediated degradation of SAMHD1 improve prime editing efficiency in HSPCs, especially when coupled with editing approaches that evade mismatch repair.
    DOI:  https://doi.org/10.1038/s41587-024-02266-4
  24. Br J Cancer. 2024 May 28.
    PARP inhibition leads to synthetic lethality with key splicing-factor mutations in myelodysplastic syndromes.
    Fangliang Zhang, Jianai Sun, Lei Zhang, Ruiqi Li, Yanzhen Wang, Huichao Geng, Chao Shen, Ling Li, Liang Chen.
       BACKGROUND: Splicing factors are frequently mutated in patients with myelodysplastic syndromes and acute myeloid leukaemia. Recent studies have revealed convergent molecular defects caused by splicing factor mutations, among which R-loop dysregulation and resultant genome instability are suggested as contributing factors to disease progression. On the other hand, understanding how mutant cells survive upon aberrant R-loop formation and genome instability is essential for developing novel therapeutics.
    METHODS: The immunoprecipitation was performed to identify R-loops in association with PARP1/poly-ADP-ribosylation. The western blot, immunofluorescence, and flow cytometry assays were used to test the cell viability, cell cycle arrest, apoptosis, and ATM activation in mutant cells following the treatment of the PARP inhibitor. The Srsf2(P95H) knock-in murine hematopoietic cells and MLL-AF9 transformed leukaemia model were generated to investigate the potential of the PARP inhibitor as a therapy for haematological malignancies.
    RESULTS: The disease-causing mutations in SRSF2 activate PARP and elevate the overall poly-ADP-ribosylation levels of proteins in response to R-loop dysregulation. In accordance, mutant cells are more vulnerable to the PARP inhibitors in comparison to the wild-type counterpart. Notably, the synthetic lethality was further validated in the Srsf2(P95H) knock-in murine hematopoietic cell and MLL-AF9 leukaemia model.
    CONCLUSIONS: Our findings suggest that mutant cells antagonise the genome threat caused by R-loop disruption by PARP activation, thus making PARP targeting a promising therapeutic strategy for myeloid cancers with mutations in SRSF2.
    DOI:  https://doi.org/10.1038/s41416-024-02729-0
  25. NEJM Evid. 2024 Jun;3(6): EVIDoa2300362
    Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes.
    Tapan M Kadia, Meixian Huang, Naveen Pemmaraju, Hussein A Abbas, Christopher Ly, Lucia Masarova, Musa Yilmaz, Mi-Ae Lyu, Ke Zeng, Tara Sadeghi, Robin Cook, Courtney D DiNardo, Naval Daver, Ghayas C Issa, Elias Jabbour, Gautam Borthakur, Nitin Jain, Guillermo Garcia-Manero, Simrit Parmar, Christopher Flowers, Hagop Kantarjian, Srdan Verstovsek.
       BACKGROUND: An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis.
    METHODS: In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes.
    RESULTS: We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths.
    CONCLUSIONS: In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).
    DOI:  https://doi.org/10.1056/EVIDoa2300362
  26. Life Sci Alliance. 2024 Aug;pii: e202402747. [Epub ahead of print]7(8):
    Metabolic adaptation pilots the differentiation of human hematopoietic cells.
    Laëtitia Racine, Romuald Parmentier, Shreyas Niphadkar, Julie Chhun, Jean-Alain Martignoles, François Delhommeau, Sunil Laxman, Andras Paldi.
      A continuous supply of energy is an essential prerequisite for survival and represents the highest priority for the cell. We hypothesize that cell differentiation is a process of optimization of energy flow in a changing environment through phenotypic adaptation. The mechanistic basis of this hypothesis is provided by the established link between core energy metabolism and epigenetic covalent modifications of chromatin. This theory predicts that early metabolic perturbations impact subsequent differentiation. To test this, we induced transient metabolic perturbations in undifferentiated human hematopoietic cells using pharmacological inhibitors targeting key metabolic reactions. We recorded changes in chromatin structure and gene expression, as well as phenotypic alterations by single-cell ATAC and RNA sequencing, time-lapse microscopy, and flow cytometry. Our observations suggest that these metabolic perturbations are shortly followed by alterations in chromatin structure, leading to changes in gene expression. We also show that these transient fluctuations alter the differentiation potential of the cells.
    DOI:  https://doi.org/10.26508/lsa.202402747
  27. Nat Genet. 2024 May 28.
    Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells.
    Karen Grimes, Hyobin Jeong, Amanda Amoah, Nuo Xu, Julian Niemann, Benjamin Raeder, Patrick Hasenfeld, Catherine Stober, Tobias Rausch, Eva Benito, Johann-Christoph Jann, Daniel Nowak, Ramiz Emini, Markus Hoenicka, Andreas Liebold, Anthony Ho, Shimin Shuai, Hartmut Geiger, Ashley D Sanders, Jan O Korbel.
      The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age, and discovered the heterogeneous mSV landscapes of hematopoietic stem and progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional somatic structural variants, including megabase-scale segmental aneuploidies. Capitalizing on comprehensive single-cell micrococcal nuclease digestion with sequencing reference data, we conducted high-resolution cell-typing for eight hematopoietic stem and progenitor cells. Clonally expanded mSVs disrupt normal cellular function by dysregulating diverse cellular pathways, and enriching for myeloid progenitors. Our findings underscore the contribution of mSVs to the cellular and molecular phenotypes associated with the aging hematopoietic system, and establish a foundation for deciphering the molecular links between mSVs, aging and disease susceptibility in normal tissues.
    DOI:  https://doi.org/10.1038/s41588-024-01754-2
  28. Leuk Res. 2024 May 26. pii: S0145-2126(24)00095-X. [Epub ahead of print]142 107529
    Molecular prognostication for transplant decision making of patients with myelodysplastic syndromes: A retrospective single-center study.
    Annalisa Condorelli, Marco Frigeni, Giulia Quaresmini, Silvia Salmoiraghi, Chiara Pavoni, Anna Grassi, Matteo Raviglione, Alessia Civini, Alessandro Putelli, Federico Lussana, Maria Chiara Finazzi, Alessandra Algarotti, Maria Caterina Micò, Orietta Spinelli, Alessandro Rambaldi.
      Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with Myelodysplastic syndromes (MDS). For many years, the selection of patients to allogeneic HSCT has been largely based on use of the International Prognostic Scoring System-Revised (IPSS-R). However, the recent broader application of next generation sequencing in clinical practice provided an abundance of molecular data and led to the introduction of molecular prognostic scores as IPSS-Molecular (IPSS-M). In this paper, we retrospectively analyzed the outcomes of 57 consecutive MDS patients treated with allogeneic HSCT in our center. Re-stratification from IPSS-R to IPSS-M occurred in almost half of patients. The application of IPSS-M to our cohort demonstrated a stronger prognostic separation compared to IPSS-R and improved the C-index. Very high-risk IPSS-M patients showed worse outcomes following HSCT compared to high-risk patients. This study provides data supporting the need of integrating molecular information in the transplant decision making of patients with MDS. This allows an earlier and better identification of patients to whom the transplant should be advised.
    Keywords:  Hematopoietic stem cell transplantation; Myelodysplastic syndromes; Prognosis; Somatic mutations
    DOI:  https://doi.org/10.1016/j.leukres.2024.107529
  29. Lancet Haematol. 2024 Jun;pii: S2352-3026(24)00098-X. [Epub ahead of print]11(6): e448-e458
    Donor lymphocyte infusion after allogeneic haematopoietic cell transplantation for haematological malignancies: basic considerations and best practice recommendations from the EBMT.
    Practice Harmonization and Guidelines Committee and the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
      Since the early description of three patients with relapsed leukaemia after allogeneic haematopoietic cell transplantation (HCT) who obtained complete remission after donor lymphocyte infusions (DLIs), the added value of this procedure to induce or maintain graft-versus-leukaemia immunity has been undisputed. For more than 30 years, DLIs have become common practice as prophylactic, pre-emptive, or therapeutic immunotherapy. However, as with many aspects of allogeneic HCT, centres have developed their own routines and practices, and many questions related to the optimal applications and toxicity, or to the immunobiology of DLI induced tumour-immunity, remain. As a part of the Practice Harmonization and Guidelines Committee and the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation effort, a panel of experts with clinical and translational knowledge in transplantation immunology and cellular therapy met during a 2-day workshop in September, 2023, in Lille, France, and developed a set of consensus-based recommendations for the application of unmanipulated DLI after allogeneic HCT for haematological malignancies. Given the absence of prospective data in the majority of publications, these recommendations are mostly based on retrospective studies and expert consensus.
    DOI:  https://doi.org/10.1016/S2352-3026(24)00098-X
  30. Nat Immunol. 2024 May 30.
    Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells.
    Joana Carrelha, Stefania Mazzi, Axel Winroth, Michael Hagemann-Jensen, Christoph Ziegenhain, Kari Högstrand, Masafumi Seki, Margs S Brennan, Madeleine Lehander, Bishan Wu, Yiran Meng, Ellen Markljung, Ruggiero Norfo, Hisashi Ishida, Karin Belander Strålin, Francesca Grasso, Christina Simoglou Karali, Affaf Aliouat, Amy Hillen, Edwin Chari, Kimberly Siletti, Supat Thongjuea, Adam J Mead, Sten Linnarsson, Claus Nerlov, Rickard Sandberg, Tetsuichi Yoshizato, Petter S Woll, Sten Eirik W Jacobsen.
      Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge.
    DOI:  https://doi.org/10.1038/s41590-024-01845-6
  31. Am J Hematol. 2024 May 27.
    Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia.
    Tamer Othman, Shanpeng Li, Jianying Zhang, Hoda Pourhassan, Vaibhav Agrawal, Dat Ngo, Jason Chen, Leonardo Farol, Firoozeh Sahebi, Karamjeet Sandhu, Ricardo Spielberger, Guido Marcucci, Stephen J Forman, Anthony S Stein, Ryotaro Nakamura, Vinod Pullarkat, Matthew Mei, Ibrahim Aldoss, Paul Koller.
      Improved first progression-free survival following allogeneic hematopoietic cell transplantation relapse with the use of immunotherapy.
    DOI:  https://doi.org/10.1002/ajh.27365
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