bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–12–03
fifty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax.
  2. FLT3-targeted therapy restores GATA1 pathway function in NPM1/FLT3-ITD mutated acute myeloid leukaemia.
  3. Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions.
  4. Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.
  5. Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.
  6. Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias.
  7. FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation.
  8. Linking GATA2 to Myeloid Dysplasia and Complex Cytogenetics in Adult Myelodysplastic Neoplasm and Acute Myeloid Leukemia.
  9. A Markov analysis of azacitidine and venetoclax versus induction chemotherapy for medically-fit patients with AML.
  10. Venetoclax-based low intensity therapy in molecular failure of NPM1 mutated AML.
  11. Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG).
  12. The management of myelofibrosis: A British Society for Haematology Guideline.
  13. Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.
  14. UBTF Tandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis.
  15. Clearing the way for new therapies in clonal hematopoiesis.
  16. Genetic features and outcomes of allogeneic transplant in patients with WT1-mutated myeloid neoplasms.
  17. Young patients with myelofibrosis have distinct clinicomolecular features, favorable prognosis, and commonly exhibit inflammatory comorbidities.
  18. A randomised evaluation of low-dose cytosine arabinoside plus lenalidomide versus single-agent low-dose cytosine arabinoside in older patients with acute myeloid leukaemia: Results from the LI-1 trial.
  19. Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
  20. SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.
  21. Outcomes of venetoclax combined with homoharringtonine and cytarabine in fit adults patients with de novo adverse-risk acute myeloid leukaemia: A single-centre retrospective analysis.
  22. SOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies.
  23. Practical considerations in clinical application of WHO 5th and ICC classification schemes for acute myeloid leukemia.
  24. Lineage Switching Occurs Upon Relapse in Pediatric Acute Myeloid Leukemia.
  25. Identifying Bone Marrow Microenvironmental Populations in Myelodysplastic Syndrome and Acute Myeloid Leukemia.
  26. Test then erase? Current status and future opportunities for Measurable Residual Disease testing in Acute Myeloid Leukemia.
  27. JAK2V617F Mutation and Associated Chromosomal Alterations in Primary and Secondary Myelofibrosis and Post-HCT Outcomes.
  28. ABC transporters are predictors of treatment failure in acute myeloid leukaemia.
  29. RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment.
  30. Early liver complications after allogeneic haematopoietic stem cell transplantation in patients with myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of the EBMT.
  31. The exon-junction complex helicase eIF4A3 holds therapeutic potential in acute myeloid leukemia.
  32. Low-dose decitabine for previously untreated acute myeloid leukemia ineligible for intensive chemotherapy aged 65 years or older: a prospective study based on comprehensive geriatric assessment.
  33. Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study.
  34. The future of HOXA-expressing leukemias: Menin inhibitor response and resistance.
  35. Insight into the mechanism of AML del(9q) progression: hnRNP K targets the myeloid master regulators CEBPA (C/EBPα) and SPI1 (PU.1).
  36. Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens.
  37. Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow.
  38. Deep generative model deciphers derailed trajectories in acute myeloid leukemia.
  39. A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents.
  40. Characterization of a novel IDH2-R159H mutation in acute myeloid leukaemia: Effects on cell metabolism and differentiation.
  41. Clonal evolution of leukemia from G6PD studies.
  42. Understanding Genetic Heterogeneity in Gene-Edited HSC Products.
  43. Characteristics and long-term outcome in a large series of chronic myelomonocytic leukaemia patients including 104 formerly referred to as oligomonocytic.
  44. CK2β Regulates Hematopoietic Stem Cell Biology and Erythropoiesis.
  45. ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS.
  46. SRSF2 mutation cooperates with ASXL1 truncated alteration to accelerate leukemogenesis.
  47. Prognostic Significance of Measurable Residual Disease Detection by Flow Cytometry in Autologous Stem Cell Apheresis Products in AML.
  48. Pathogenic DDX41 variants, possible response predictors to low-dose melphalan in hypo- and normocellular MDS and AML.
  49. The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells.
  50. Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS-a study of the CMWP of the EBMT.
  51. Integration of Transcriptomic Features to Improve Prognosis Prediction of Pediatric Acute Myeloid Leukemia With KMT2A Rearrangement.
  52. Persistence of UBTF tandem duplications in remission in acute myeloid leukaemia.
  1. Leukemia. 2023 Nov 25.
    TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax.
    Anudishi Tyagi, Appalaraju Jaggupilli, Stanley Ly, Bin Yuan, Fouad El-Dana, Venkatesh L Hegde, Vivek Anand, Bijender Kumar, Mamta Puppala, Zheng Yin, Stephen T C Wong, Alexis Mollard, Hariprasad Vankayalapati, Jason M Foulks, Steven L Warner, Naval Daver, Gautam Borthakur, V Lokesh Battula.
      We identified activin A receptor type I (ACVR1), a member of the TGF-β superfamily, as a factor favoring acute myeloid leukemia (AML) growth and a new potential therapeutic target. ACVR1 is overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression sensitized AML cells to FLT3 inhibitors. We developed a novel ACVR1 inhibitor, TP-0184, which selectively caused growth arrest in FLT3-mutated AML cell lines. Molecular docking and in vitro kinase assays revealed that TP-0184 binds to both ACVR1 and FLT3 with high affinity and inhibits FLT3/ACVR1 downstream signaling. Treatment with TP-0184 or in combination with BCL2 inhibitor, venetoclax dramatically inhibited leukemia growth in FLT3-mutated AML cell lines and patient-derived xenograft models in a dose-dependent manner. These findings suggest that ACVR1 is a novel biomarker and plays a role in AML resistance to FLT3 inhibitors and that FLT3/ACVR1 dual inhibitor TP-0184 is a novel potential therapeutic tool for AML with FLT3 mutations.
    DOI:  https://doi.org/10.1038/s41375-023-02086-6
  2. EJHaem. 2023 Nov;4(4): 1100-1104
    FLT3-targeted therapy restores GATA1 pathway function in NPM1/FLT3-ITD mutated acute myeloid leukaemia.
    D Sorcini, A Stella, A Scialdone, S Sartori, A Marra, R Rossi, F De Falco, F M Adamo, E Dorillo, C Geraci, R Arcaleni, C Rompietti, A Esposito, L Moretti, M G Mameli, M P Martelli, B Falini, P Sportoletti.
      One-third of newly diagnosed adult acute myeloid leukaemia (AML) carry FLT3 mutations, which frequently occur together with nucleophosmin (NPM1) mutations and are associated with worse prognosis. FLT3 inhibitors are widely used in clinics with limitations due to drug resistance. AML cells carrying FLT3 mutations in both mouse models and patients present low expression of GATA1, a gene involved in haematopoietic changes preceding AML. Here, we show that FLT3 inhibition induces cellular responses and restores the GATA1 pathway and functions in NPM1/FLT3-ITD mutated AML, thus providing a new mechanism of action for this drug.
    Keywords:  FLT3 inhibitors; FLT3‐ITD; GATA1; acute myeloid leukaemia; heamatological malignancies; leukaemia therapy
    DOI:  https://doi.org/10.1002/jha2.738
  3. EJHaem. 2023 Nov;4(4): 1059-1070
    Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions.
    Shyam A Patel, Jan Cerny, William K Gerber, Muthalagu Ramanathan, Asiri Ediriwickrema, Benjamin Tanenbaum, Lloyd Hutchinson, Xiuling Meng, Julie Flahive, Bruce Barton, Andrew J Gillis-Smith, Sakiko Suzuki, Salwa Khedr, William Selove, Anne W Higgins, Patricia M Miron, Karl Simin, Bruce Woda, Jonathan M Gerber.
      TP53 aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with TP53 aberrations. We observed no significant differences between MDS and AML regarding TP53 genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus TP53 variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, p = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, p = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, p = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, p = 0.0009). Clonal dynamic modeling showed a significant reduction in TP53 VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of TP53-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.
    Keywords:  TP53; acute myeloid leukemia; clonal dynamics; hematopoietic stem cell; myelodysplastic syndrome
    DOI:  https://doi.org/10.1002/jha2.791
  4. Eur J Haematol. 2023 Nov 29.
    Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.
    C Petit, C Saillard, B Mohty, Y Hicheri, F Villetard, V Maisano, A Charbonnier, J Rey, E D'Incan, C Rouzaud, V Gelsi-Boyer, A Murati, A C Lhoumeau, A Ittel, M J Mozziconacci, A S Alary, M-A Hospital, N Vey, S Garciaz.
       OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML).
    METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021.
    RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates.
    CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.
    Keywords:  acute myeloide leukemia; azacitidine; refractory; relapse; venetoclax
    DOI:  https://doi.org/10.1111/ejh.14140
  5. Blood Adv. 2023 Nov 21. pii: bloodadvances.2023011165. [Epub ahead of print]
    Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.
    Kai Yu, Natalie T Deuitch, Matthew Douglas Merguerian, Lea Cunningham, Joie Davis, Erica Bresciani, Jamie L Diemer, Elizabeth J Andrews, Alice Young, Frank X Donovan, Raman Sood, Kathleen Marie Craft, Shawn N Chong, Settara C Chandrasekharappa, James Mullikin, Paul P Liu.
      Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 25 of 51 (49%) patients without hematological malignancy, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 6 other CHIP or AML driver genes (TET2, DNMT3A, KRAS, LRP1B, IDH1, and KMT2C) were also found in two or more patients without hematological malignancy. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring changes in somatic mutations and clinical manifestations prospectively may reveal mechanisms for malignant progression and inform clinical management. ClinicalTrials.gov identifier: NCT03854318.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011165
  6. Sci Adv. 2023 Dec;9(48): eadh1436
    Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias.
    Yuki Nishida, Jo Ishizawa, Edward Ayoub, Rafael Heinz Montoya, Lauren B Ostermann, Muharrem Muftuoglu, Vivian R Ruvolo, Tallie Patsilevas, Darah A Scruggs, Shayaun Khazaei, Po Yee Mak, Wenjing Tao, Bing Z Carter, Steffen Boettcher, Benjamin L Ebert, Naval G Daver, Marina Konopleva, Takahiko Seki, Kensuke Kojima, Michael Andreeff.
      The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.
    DOI:  https://doi.org/10.1126/sciadv.adh1436
  7. Clin Cancer Res. 2023 Nov 27.
    FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation.
    Ashley Woods, Kelly J Norsworthy, Xin Wang, Jonathon Vallejo, Edwin C Y Chow, Ruo-Jing Li, Jielin Sun, Rosane Charlab, Xiling Jiang, Richard Pazdur, Marc R Theoret, R Angelo de Claro.
      On May 25th, 2022, FDA approved a supplemental application for ivosidenib (Tibsovo; Servier) extending the indication in patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) in older adults or those with comorbidities to include the combination with azacitidine. The efficacy of ivosidenib in combination with azacitidine was evaluated in Study AG120-C-009, a phase 3, multicenter, double-blind, randomized (1:1), controlled study of ivosidenib or matched placebo in combination with azacitidine in adults with previously untreated AML with an IDH1 mutation who were 75 years or older or had comorbidities that precluded use of intensive induction chemotherapy. Efficacy was established based on improved event-free survival (EFS) and overall survival (OS) on the ivosidenib + azacitidine arm (HR 0.35, 95% CI 0.17, 0.72, p= 0.0038 and HR 0.44, 95% CI 0.27, 0.73, p=0.0010), respectively. Furthermore, the rate and duration of complete remission (CR) were improved with ivosidenib versus placebo (CR 47% versus 15%, 2-sided p<0.0001; median duration of CR not estimable [NE] [95% CI 13.0, NE] months versus 11.2 [95% CI 3.2, NE] months). The safety profile of ivosidenib in combination with azacitidine was consistent with that of ivosidenib monotherapy, with important adverse reactions including differentiation syndrome (15%) and QT interval prolongation (20%).
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2234
  8. Blood Adv. 2023 Nov 29. pii: bloodadvances.2023011554. [Epub ahead of print]
    Linking GATA2 to Myeloid Dysplasia and Complex Cytogenetics in Adult Myelodysplastic Neoplasm and Acute Myeloid Leukemia.
    Daniel J Robbins, Tatiana S Pavletich, Apoorva T Patil, Demetra C Pahopos, Michael Lasarev, Usha S Polaki, Zhubin J Gahvari, Emery H Bresnick, Daniel R Matson.
      GATA Binding Protein 2 (GATA2) is a conserved zinc finger transcription factor that regulates the emergence and maintenance of complex genetic programs driving development and function of hematopoietic stem and progenitor cells (HSPCs). Patients born with monoallelic GATA2 mutations develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML) while acquired GATA2 mutations are reported in 3-5% of sporadic AML cases. The mechanisms by which aberrant GATA2 activity promotes MDS and AML are incompletely understood. Efforts to understand GATA2 in basic biology and disease will be facilitated by the development of broadly efficacious antibodies recognizing physiologic levels of GATA2 in diverse tissue types and assays. Here, we purified a polyclonal anti-GATA2 antibody and generated multiple highly specific anti-GATA2 monoclonal antibodies, optimized them for immunohistochemistry (IHC) on patient bone marrow biopsies, and analyzed GATA2 expression in adults with healthy bone marrow, MDS, and acute leukemia. In healthy bone marrow, GATA2 was detected in mast cells, subsets of CD34+ HSPCs, E-cadherin+ erythroid progenitors, and megakaryocytes. In MDS, GATA2 expression tracks with bone marrow blast percentage, positively correlates with myeloid dysplasia and complex cytogenetics, and is a non-independent negative predictor of overall survival. In acute leukemia, percent GATA2+ blasts closely associates with myeloid lineage, while a subset of lymphoblastic and undifferentiated leukemias with myeloid features also express GATA2. However, percent of GATA2+ blasts in AML is highly variable. Elevated GATA2 expression in AML blasts correlates with peripheral neutropenia and complex AML cytogenetics but unlike in MDS does not predict survival.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011554
  9. Blood Adv. 2023 Nov 29. pii: bloodadvances.2023011219. [Epub ahead of print]
    A Markov analysis of azacitidine and venetoclax versus induction chemotherapy for medically-fit patients with AML.
    Mithunan Ravindran, Lee Mozessohn, Matthew C Cheung, Rena J Buckstein, Jennifer Teichman.
      While induction chemotherapy (IC) is the standard of care in medically-fit patients with newly diagnosed acute myeloid leukemia (AML), limited retrospective data indicate that adverse risk patients may benefit from azacitidine and venetoclax (aza-ven). Our goal was to perform a Markov decision analysis to determine whether IC or aza-ven is the optimal induction regimen in this population. Using the TreeAge software, Markov models were created for adverse risk and intermediate risk cohorts. A systematic review of the literature informed the transition probabilities and utilities included in the analyses. Our primary outcome was quality adjusted life years (QALY) gained over five years following diagnosis. Overall, adverse risk patients treated with IC gained 1.4 QALY, compared to 2.0 QALY in patients treated with aza-ven. Adverse risk patients treated with IC and allogeneic stem cell transplant (AlloSCT), IC, aza-ven and AlloSCT, and aza-ven gained 2.1, 1.5, 3.0, and 1.9 QALY, respectively. Meanwhile, intermediate risk patients treated with IC gained 2.0 QALY, compared to 1.7 QALY in patients treated with aza-ven. Intermediate risk patients treated with IC and AlloSCT, IC, aza-ven and AlloSCT, and aza-ven gained 2.7, 2.3, 2.6, and 1.8 QALY, respectively. We have demonstrated that medically-fit patients with newly diagnosed adverse risk AML may benefit from treatment with aza-ven over IC, while IC remains the preferred approach for intermediate risk patients. Our work challenges the use of the European LeukemiaNet risk classification in patients treated with aza-ven and highlights the need for prospective investigation into aza-ven as induction therapy for medically-fit patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011219
  10. Blood Adv. 2023 Dec 01. pii: bloodadvances.2023011106. [Epub ahead of print]
    Venetoclax-based low intensity therapy in molecular failure of NPM1 mutated AML.
    Carlos Jimenez Chillon, Jad Othman, David Taussig, Carlos Jiménez-Vicente, Alexandra Martínez-Roca, Ing Soo Tiong, Manish Jain, James Aries, Seda Cakmak, Steven Knapper, Daniel Tuyet Kristensen, Vidhya Murthy, Zacharoula Galani, Charlotte Kallmeyer, Loretta Ngu, David Veale, Simon Bolam, Nina Orfali, Anne Parker, Cara Manson, Jane Parker, Thomas Erblich, Deborah Susan Richardson, Katya Mokretar, Nicola Potter, Ulrik Malthe Overgaard, Anne Stidsholt Roug, Andrew H Wei, Jordi Esteve, Martin Jädersten, Nigel H Russell, Richard Dilon.
      Molecular failure in NPM1 mutated AML inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here we report an international multicentre cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66/79 (84%) and MRD negativity in 56/79 (71%). 18/79 (23%) patients required hospitalisation and no deaths were reported during treatment. 41 patients were bridged to allogeneic transplant with no further therapy and 25/41 were MRD negative assessed by RT-qPCR before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45% and in responding patients there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs. 91%, p<0.01), worse OS (HR 2.50, 95% CI 1.06-5.86, p=0.036) and EFS (HR 1.87, 95% CI 1.06-3.28, p=0.03). 18/35 non-transplanted patients became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1 mutated AML, either as a bridge to transplant or as definitive therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011106
  11. Leukemia. 2023 Nov 28.
    Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG).
    Michael Ozga, Deedra Nicolet, Krzysztof Mrózek, Ayse S Yilmaz, Jessica Kohlschmidt, Karilyn T Larkin, James S Blachly, Christopher C Oakes, Jill Buss, Christopher J Walker, Shelley Orwick, Vindi Jurinovic, Maja Rothenberg-Thurley, Annika Dufour, Stephanie Schneider, Maria Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E Berdel, Bernhard J Woermann, Wolfgang Hiddemann, Jan Braess, Marion Subklewe, Karsten Spiekermann, Andrew J Carroll, William G Blum, Bayard L Powell, Jonathan E Kolitz, Joseph O Moore, Robert J Mayer, Richard A Larson, Geoffrey L Uy, Wendy Stock, Klaus H Metzeler, H Leighton Grimes, John C Byrd, Nathan Salomonis, Tobias Herold, Alice S Mims, Ann-Kathrin Eisfeld.
      Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients' sex in analyses of AML biology and prognostication.
    DOI:  https://doi.org/10.1038/s41375-023-02068-8
  12. Br J Haematol. 2023 Dec 01.
    The management of myelofibrosis: A British Society for Haematology Guideline.
    BSH Committee
      
    Keywords:  JAK; management; myelofibrosis; transplantation
    DOI:  https://doi.org/10.1111/bjh.19186
  13. Bone Marrow Transplant. 2023 Dec 02.
    Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.
    Jesús Duque-Afonso, Jürgen Finke, Maud Ngoya, Jacques-Emmanuel Galimard, Charles Craddock, Kavita Raj, Adrian Bloor, Emma Nicholson, Matthias Eder, Orchard Kim, Thomas Valerius, John A Snowden, Eleni Tholouli, Charles Crawley, Matthew Collin, Keith M O Wilson, Alain Gadisseur, Rachel Protheroe, Eva Maria Wagner-Drouet, Bipin N Savani, Alexandros Spyridonidis, Fabio Ciceri, Arnon Nagler, Mohamad Mohty.
      Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
    DOI:  https://doi.org/10.1038/s41409-023-02150-w
  14. medRxiv. 2023 Nov 13. pii: 2023.11.13.23298320. [Epub ahead of print]
    UBTF Tandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis.
    Juan M Barajas, Masayuki Umeda, Lisett Contreras, Mahsa Khanlari, Tamara Westover, Michael P Walsh, Emily Xiong, Chenchen Yang, Brittney Otero, Marc Arribas-Layton, Sherif Abdelhamed, Guangchun Song, Xiaotu Ma, Melvin E Thomas, Jing Ma, Jeffery M Klco.
      Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor ( UBTF ). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF -TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF . We demonstrate that UBTF- TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that UBTF -TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF- TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.
    Key Points: Largest cohort of pediatric UBTF- TD in myeloid neoplasms reported to date. Use of single-cell DNA+protein sequencing technology in 3 UBTF- TD samples reveals a clonal evaluation pattern characterized by sequential acquisition of WT1 and FLT3 mutations and a more stem cell-like protein expression pattern. Pediatric MDS and AML patients with UBTF- TD alterations dysplastic features with an increase erythroid precursors. Tandem duplications in exon 9 of UBTF represent a rare but functionally equivalent subgroup of UBTF- TD myeloid neoplasms.
    Impact Statement: UBTF tandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatric UBTF -TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.
    DOI:  https://doi.org/10.1101/2023.11.13.23298320
  15. Blood Adv. 2023 Nov 28. 7(22): 7151-7152
    Clearing the way for new therapies in clonal hematopoiesis.
    Victoria Y Ling, Steven W Lane.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023011728
  16. Blood Adv. 2023 Nov 27. pii: bloodadvances.2023010960. [Epub ahead of print]
    Genetic features and outcomes of allogeneic transplant in patients with WT1-mutated myeloid neoplasms.
    Anmol Baranwal, Rami Basmaci, Rong He, David S Viswanatha, Patricia T Greipp, Hemant S Murthy, James M Foran, Jeanne M Palmer, William J Hogan, Mark R Litzow, Mehrdad Hefazi, Abhishek A Mangaonkar, Mithun Vinod Shah, Aref Al-Kali, Hassan B Alkhateeb.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023010960
  17. Ann Hematol. 2023 Nov 30.
    Young patients with myelofibrosis have distinct clinicomolecular features, favorable prognosis, and commonly exhibit inflammatory comorbidities.
    Nathan P Horvat, Enas F Abdallah, Zhuoer Xie, Najla Al Ali, Seongseok Yun, Alison Walker, Eric Padron, David Sallman, Onyee Chan, Jeffrey Lancet, Rami Komrokji, Andrew T Kuykendall.
      Myelofibrosis (MF) is commonly diagnosed in older individuals and has not been extensively studied in young patients. Given the infrequent diagnosis in young patients, analyzing this cohort may identify factors that predict for disease development/progression. We retrospectively analyzed clinical/genomic characteristics, treatments, and outcomes of patients with MF aged 18-50 years (YOUNG) at diagnosis. Sixty-three YOUNG patients were compared to 663 patients diagnosed at 51 or older (OLDER). YOUNG patients were more likely to be female, harbor driving CALR mutations, lack splicing gene mutations, and have low-risk disease by dynamic international prognostic scoring system (DIPSS) at presentation. Thirty-six patients (60%) presented with incidental lab findings and 19 (32%) with symptomatic disease. Median time to first treatment was 9.4 months (mo). Fourteen (22%) YOUNG patients underwent allogeneic hematopoietic stem cell transplant (median 57.4 mo post-diagnosis). Five (8%) developed blast-phase disease (median 99 mo post-diagnosis). Median overall survival (OS) for YOUNG patients was not reached compared to 62.8 mo in OLDER cohort (p < 0.001). The survival advantage for YOUNG patients lost significance when compared to OLDER patients lacking splicing mutations (p = 0.11). Thirty-one (49%) had comorbidities predating MF diagnosis. Presence of a comorbidity correlated with increased disease risk as measured by serial DIPSS (p=0.02). Increased disease risk correlated with decreased OS (p = 0.05). MF is rare in young adults, has distinct clinical/molecular correlates, and a favorable prognosis. The high frequency of inflammatory comorbidities and their correlation with progression of disease risk clinically highlights the role of inflammation in MF pathogenesis.
    Keywords:  Genomic data; JAK2 inhibitors; Myelofibrosis; Myeloproliferative neoplasms; Primary myelofibrosis; Secondary myelofibrosis
    DOI:  https://doi.org/10.1007/s00277-023-05564-0
  18. Br J Haematol. 2023 Nov 28.
    A randomised evaluation of low-dose cytosine arabinoside plus lenalidomide versus single-agent low-dose cytosine arabinoside in older patients with acute myeloid leukaemia: Results from the LI-1 trial.
    UK NCRI AML Study Group
      Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI-1 trial, we evaluated lenalidomide (LEN) in combination with low-dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements.
    Keywords:  acute myeloid leukaemia; clinical trial; elderly; lenalidomide; low-dose cytosine arabinoside
    DOI:  https://doi.org/10.1111/bjh.19220
  19. EMBO J. 2023 Nov 27. e112348
    Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
    Yu Wei Zhang, Katharina Schönberger, Nina Cabezas-Wallscheid.
      During the last decades, remarkable progress has been made in further understanding the complex molecular regulatory networks that maintain hematopoietic stem cell (HSC) function. Cellular and organismal metabolisms have been shown to directly instruct epigenetic alterations, and thereby dictate stem cell fate, in the bone marrow. Epigenetic regulatory enzymes are dependent on the availability of metabolites to facilitate DNA- and histone-modifying reactions. The metabolic and epigenetic features of HSCs and their downstream progenitors can be significantly altered by environmental perturbations, dietary habits, and hematological diseases. Therefore, understanding metabolic and epigenetic mechanisms that regulate healthy HSCs can contribute to the discovery of novel metabolic therapeutic targets that specifically eliminate leukemia stem cells while sparing healthy HSCs. Here, we provide an in-depth review of the metabolic and epigenetic interplay regulating hematopoietic stem cell fate. We discuss the influence of metabolic stress stimuli, as well as alterations occurring during leukemic development. Additionally, we highlight recent therapeutic advancements toward eradicating acute myeloid leukemia cells by intervening in metabolic and epigenetic pathways.
    Keywords:  acute myeloid leukemia; epigenetics; hematopoietic stem cells; leukemia stem cells; metabolism
    DOI:  https://doi.org/10.15252/embj.2022112348
  20. Blood Cancer J. 2023 Nov 27. 13(1): 171
    SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.
    Yue Yang, Salar Abbas, Mohammad A Sayem, Avik Dutta, Golam Mohi.
      SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2 mutation in JAK2V617F-driven MPN remains elusive. To investigate the consequences of SRSF2P95H and JAK2V617F mutations in MPN, we generated Cre-inducible Srsf2P95H/+Jak2V617F/+ knock-in mice. We show that co-expression of Srsf2P95H mutant reduced red blood cell, neutrophil, and platelet counts, attenuated splenomegaly but did not induce bone marrow fibrosis in Jak2V617F/+ mice. Furthermore, co-expression of Srsf2P95H diminished the competitiveness of Jak2V617F mutant hematopoietic stem/progenitor cells. We found that Srsf2P95H mutant reduced the TGF-β levels but increased the expression of S100A8 and S100A9 in Jak2V617F/+ mice. Furthermore, enforced expression of S100A9 in Jak2V617F/+ mice bone marrow significantly reduced the red blood cell, hemoglobin, and hematocrit levels. Overall, these data suggest that concurrent expression of Srsf2P95H and Jak2V617F mutants reduces erythropoiesis but does not promote the development of bone marrow fibrosis in mice.
    DOI:  https://doi.org/10.1038/s41408-023-00947-y
  21. EJHaem. 2023 Nov;4(4): 1208-1211
    Outcomes of venetoclax combined with homoharringtonine and cytarabine in fit adults patients with de novo adverse-risk acute myeloid leukaemia: A single-centre retrospective analysis.
    Bao-Quan Song, Xin Kong, Yan Pu, Yin Liu, Jian Zhang, De-Pei Wu, Hui-Ying Qiu.
      Adverse-risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine (HHT) plus cytarabine (VHA) regimen for de novo adverse-risk AML. Thirteen de novo AML patients with adverse-risk factors were treated with venetoclax (100 mg day 1, 200 mg day 2, 400 mg days 3-21), HHT (1 mg/m2 days 1-5) and cytarabine (100 mg/m2 days 1-5) (VHA regimen). Complete remission (CR) was achieved in 11/13 patient (84.6%), all of CR responders were measurable residual disease (MRD) negative detected by multi-parameter flow cytometry (MFC). Grade 3-4 neutropenia, anaemia, and thrombocytopenia occurred in most patients. Grade 3-4 non haematological adverse events (AEs) included febrile neutropenia (4/13, 30.8%). With a median follow-up of 10 months (range 4-19), median overall survival and event-free survival were not reached. VHA may be a promising and well-tolerated regimen in de novo adverse-risk AML.
    Keywords:  Acute myeloid leukemia; Adverse‐risk; Cytarabine; Homoharringtonine; Venetoclax
    DOI:  https://doi.org/10.1002/jha2.792
  22. Clin Lymphoma Myeloma Leuk. 2023 Oct 21. pii: S2152-2650(23)02150-X. [Epub ahead of print]
    SOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies.
    Mark Forsberg, Marina Konopleva.
      The discovery of Venetoclax (VEN) has transformed the therapeutic landscape of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). However, the response is heterogeneous with 10% to 50% of newly diagnosed AML patients not responding to hypomethylating agent (HMA) and VEN. Furthermore, up to 40% of responding patients relapse shortly. This review discusses the mechanism of action of Venetoclax and the major mechanisms of inherent and acquired resistance to VEN. VEN is highly specific to BCL-2 binding, as such other antiapoptotic proteins in BCL-2 family induce resistance. These antiapoptotic proteins can also be upregulated via a number of compensatory cell signaling pathways including PI3K/AKT/mTOR, the MAPK/ERK pathway, and mutant FLT3-ITD. Mutations can occur in BCL-2 and BAX proteins, or they can be silenced by TP53 mutations and other epigenetic changes. Changes to mitochondrial structure and metabolism can induce resistance. Key metabolic regulators include OXPHOS and alternative amino acid metabolism. Finally microenvironmental factors can influence VEN responses. This paper evaluates subsets of AML by differentiation, histology, cytogenetics and molecular markers and their different responses to VEN; with spliceosome mutations, ASXL1, NPM1 and IDH1/2 being favorable while others such as FLT3, TP53 and BCL-2 mutations being less responsive. Currently intensive multiagent chemotherapy and Venetoclax combinations such as 7+3+VEN are favored in fit younger AML patients. However, with resistant patients' subsets targeted combination therapies are becoming an increasingly attractive option. We explore the incorporation of non-BCL-2 inhibitors, next-generation BCL-2 and multi-protein agents, other inhibitors most prominently FLT-3 inhibitors in addition to Venetoclax, and other novel approaches for resolving Venetoclax resistance.
    Keywords:  AML; BCL-2; CLL; Drug-resistance; Venetoclax
    DOI:  https://doi.org/10.1016/j.clml.2023.10.006
  23. Blood Rev. 2023 Nov 25. pii: S0268-960X(23)00123-6. [Epub ahead of print] 101156
    Practical considerations in clinical application of WHO 5th and ICC classification schemes for acute myeloid leukemia.
    Daniel J Chandra, Curtis A Lachowiez, Sanam Loghavi.
      The updated WHO 5th edition and ICC 2022 classification systems for AML aim to refine our diagnostic criteria and definitions of AML with deeper incorporation of cytogenetic and molecular aberrations. The two classification systems diverge, however, in numerous AML defining criteria and subclassifications, including the incorporation of blast enumeration and the integration of specific genomic mutations. These differences often create challenges for clinicians in not only establishing a diagnosis of AML, but also in determining the best treatment plan for patients. In this review, we highlight the literature surrounding the contrasting areas between the WHO and ICC guidelines and offer guidance in the clinical application of these guidelines in the management of patients with AML.
    Keywords:  AML; ICC; WHO
    DOI:  https://doi.org/10.1016/j.blre.2023.101156
  24. Cancer Discov. 2023 Dec 01. OF1
    Lineage Switching Occurs Upon Relapse in Pediatric Acute Myeloid Leukemia.
      Relapsed tumors in pediatric AML are enriched in primitive cells and lose myeloid transcriptional programs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-187
  25. J Vis Exp. 2023 Nov 10.
    Identifying Bone Marrow Microenvironmental Populations in Myelodysplastic Syndrome and Acute Myeloid Leukemia.
    Christina M Kaszuba, Benjamin J Rodems, Sonali Sharma, Edgardo I Franco, John M Ashton, Laura M Calvi, Jeevisha Bajaj.
      The bone marrow microenvironment consists of distinct cell populations, such as mesenchymal stromal cells, endothelial cells, osteolineage cells, and fibroblasts, which provide support for hematopoietic stem cells (HSCs). In addition to supporting normal HSCs, the bone marrow microenvironment also plays a role in the development of hematopoietic stem cell disorders, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). MDS-associated mutations in HSCs lead to a block in differentiation and progressive bone marrow failure, especially in the elderly. MDS can often progress to therapy-resistant AML, a disease characterized by a rapid accumulation of immature myeloid blasts. The bone marrow microenvironment is known to be altered in patients with these myeloid neoplasms. Here, a comprehensive protocol to isolate and phenotypically characterize bone marrow microenvironmental cells from murine models of myelodysplastic syndrome and acute myeloid leukemia is described. Isolating and characterizing changes in the bone marrow niche populations can help determine their role in disease initiation and progression and may lead to the development of novel therapeutics targeting cancer-promoting alterations in the bone marrow stromal populations.
    DOI:  https://doi.org/10.3791/66093
  26. Acta Haematol. 2023 Nov 30.
    Test then erase? Current status and future opportunities for Measurable Residual Disease testing in Acute Myeloid Leukemia.
    Amanda L Blackmon, Christopher S Hourigan.
       BACKGROUND: Measurable residual disease (MRD) test positivity during and after treatment in patients with acute myeloid leukemia (AML) has been associated with higher rates of relapse and worse overall survival. Current approaches for MRD testing are not standardized leading to inconsistent results and poor prognostication of disease. Pertinent studies evaluating AML MRD testing at specific times points, with various therapeutics and testing methods are presented.
    SUMMARY: AML is a set of diseases with different molecular and cytogenetic characteristics, and is often polyclonal with evolution over time. This genetic diversity poses a great challenge for a single AML MRD testing approach. The current ELN 2021 MRD guidelines recommend MRD testing by quantitative polymerase chain reaction (qPCR) in those with a validated molecular target or multiparameter flow cytometry (MFC) in all other cases. The benefit of MFC is the ability to use this method across disease subsets, at the relative expense of suboptimal sensitivity and specificity. AML MRD detection may be improved with molecular methods. Genetic characterization at AML diagnosis and relapse is now standard of care for appropriate therapeutic assignment, future initiatives will provide the evidence to support testing in remission to direct clinical interventions.
    KEY MESSAGES: The treatment options for patients with AML have expanded for specific molecular subsets such as FLT3 and IDH1/2 mutated AML, with development of novel agents for NPM1 mutated or KMT2A rearranged AML ongoing, but also due to effective venetoclax-combinations. Evidence regarding highly sensitive molecular MRD detection methods for specific molecular subgroups, in the context of these new treatment approaches, will likely shape the future of AML care.
    DOI:  https://doi.org/10.1159/000535463
  27. Blood Adv. 2023 Oct 27. pii: bloodadvances.2023010882. [Epub ahead of print]
    JAK2V617F Mutation and Associated Chromosomal Alterations in Primary and Secondary Myelofibrosis and Post-HCT Outcomes.
    Maryam Rafati, Derek Brown, Weiyin Zhou, Kristine M Jones, Wen Luo, Andrew St Martin, Youjin Wang, Meilun He, Stephen R Spellman, Tao Wang, H Joachim Deeg, Vikas Gupta, Stephanie J Lee, Yung-Tsi Bolon, Stephen J Chanock, Mitchell J Machiela, Wael Saber, Shahinaz M Gadalla.
      JAK2V617F is the most common driver mutation in primary or secondary myelofibrosis in which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N=973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and SNP-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 MF patients (634 primary MF [PMF], 135 post-polycythemia vera [PPV-MF], and 155 post-essential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, non-relapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; HR=7.65, 95% CI=2.10-27.82, p=0.002). Yet, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in MF patients, particularly for PMF and PPV-MF.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010882
  28. Biomed Pharmacother. 2023 Nov 30. pii: S0753-3322(23)01728-6. [Epub ahead of print]170 115930
    ABC transporters are predictors of treatment failure in acute myeloid leukaemia.
    Ela Cerovska, Cyril Salek, David Kundrat, Sarka Sestakova, Adam Pesek, Ivana Brozinova, Monika Belickova, Hana Remesova.
       INTRODUCTION: To date, no chemoresistance predictors are included in acute myeloid leukaemia (AML) prognostic scoring systems to distinguish responding and refractory AML patients prior to chemotherapy. ABC transporters have been described as altering AML chemosensitivity; however, a relevant study investigating their role at various molecular levels was lacking.
    METHODS: Gene expression, genetic variants, methylation and activity of ABCA2, ABCA5, ABCB1, ABCB6, ABCC1, ABCC3 and ABCG2 were analysed in AML blasts and healthy myeloblasts. Differences between responding and refractory AML in a cohort of 113 patients treated with 3 + 7 induction therapy were explored.
    RESULTS: ABCC3 variant rs2301837 (p = 0.049), ABCG2 variant rs11736552 (p = 0.044), higher ABCA2 (p = 0.021), ABCC1 (p = 0.017), and ABCG2 expression (p = 0.023) and a higher number of concurrently overexpressed transporters (p = 0.002) were predictive of treatment failure by multivariate analysis. Expression of ABCA5 (p = 0.003), ABCB6 (p = 0.001) and ABCC3 (p < 0.0001) increased significantly after chemotherapy. Higher ABCG2 promoter methylation correlated with lower ABCG2 expression (p = 0.0001). ABCC1 was identified as the most active transporter in AML blasts by functional analysis.
    CONCLUSIONS: ABC transporters, especially ABCC1 seem to contribute substantially to AML chemoresistance. A detailed understanding of chemoresistance mechanisms and the clinical implications of chemosensitivity predictors may lead to alternative therapeutic approaches for AML patients with unveiled chemoresistance signatures.
    Keywords:  ABC transporter; Acute myeloid leukemia; Anthracycline; Chemoresistance
    DOI:  https://doi.org/10.1016/j.biopha.2023.115930
  29. Leukemia. 2023 Nov 30.
    RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment.
    Ying Chen, Jin Wen, Qian Li, Danyue Peng, Chenxi Liao, Xiao Ma, Mengyuan Wang, Jialan Niu, Di Wang, Yingnan Li, Xiaolan Zhang, Hao Zhou, Jing Zou, Lei Li, Lingbo Liu.
      The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.
    DOI:  https://doi.org/10.1038/s41375-023-02097-3
  30. Br J Haematol. 2023 Nov 28.
    Early liver complications after allogeneic haematopoietic stem cell transplantation in patients with myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of the EBMT.
    Marie Robin, Luuk Gras, Linda Koster, Nico Gagelmann, Gwendolyn van Gorkom, Matthias Ederr, Maija Itälä-Remes, Tsila Zuckerman, Yves Beguin, Nicolaas Schaap, Joanna Drozd-Sokolowska, Kavita Raj, Patrick J Hayden, Liesbeth C de Wreede, Giorgia Battipaglia, Nicola Polverelli, Tomasz Czerw, Juan Carlos Hernandez Boluda, Nicolaus Kröger, Ibrahim Yakoub-Agha, Donal P McLornan.
      
    DOI:  https://doi.org/10.1111/bjh.19214
  31. Leukemia. 2023 Nov 30.
    The exon-junction complex helicase eIF4A3 holds therapeutic potential in acute myeloid leukemia.
    Sophia Miliara, Elisabetta Cozzi, Xiangfu Zhong, Isaac Chan, Karl Ekwall, Sören Lehmann, Andreas Lennartsson, Jiri Bartek, Dimitris C Kanellis.
      
    DOI:  https://doi.org/10.1038/s41375-023-02098-2
  32. Ther Adv Hematol. 2023 ;14 20406207231208979
    Low-dose decitabine for previously untreated acute myeloid leukemia ineligible for intensive chemotherapy aged 65 years or older: a prospective study based on comprehensive geriatric assessment.
    Ru Feng, Shuai Zhang, Jiang-Tao Li, Ting Wang, Chun-Li Zhang, Jie-Fei Bai, Lei Yang, Li-Ru Wang, Hong-Mei Jing, Hui Liu.
       Background: The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate intensive chemotherapy.
    Objectives: We aimed to evaluate the efficacy of low-dose decitabine in previously untreated patients with AML aged ⩾65 years who were ineligible for intensive chemotherapy based on a comprehensive geriatric assessment.
    Design: We performed a prospective, multicenter, open-label, and non-randomized study.
    Methods: Patients were enrolled at four centers in Beijing between 1 January 2017 and 31 December 2020. They were treated with decitabine at a dose of 6 mg/m2 for 10 days. The treatment was repeated every 28 days for one cycle for a total of six cycles. The primary endpoint of our study was overall survival (OS) at the end of the first year after enrolment. The secondary endpoints included overall response rate, leukemia-free survival, relapse rate, treatment-related mortality (TRM), quality of life, safety, and transfusion dependence. Patients were continuously monitored for toxicity.
    Results: Overall, 47 patients (30 males and 17 females) participated in this study. The median age of the enrolled patients was 78 (range, 65-90) years. The median follow-up time was 22.2 (range, 4.6-38.8) months. Fifteen (31.9%) patients achieved complete remission (CR), 11 (23.4%) patients achieved partial remission, 3 (6.4%) patients achieved hematological improvement only, and 18 (38.3%) patients did not achieve remission. The median time to obtain CR was 2 months. The median CR was 8.5 months. Of the patients, 36 (76.6%) patients completed six cycles of treatment with low-dose decitabine, and the 1-year OS was 36.1%. According to instrumental activities of daily living scales, age, comorbidities, and albumin (IACA) scores, the median survival was 11.2 months in the unfit group and 6 months in the frail group. The 1-year OS rates in the unfit and frail groups were 49.2% and 23.4%, respectively. Grade ⩾3 non-hematological toxicity was observed in 70.2% (33/47) of the patients. TRM occurred in three patients. No early deaths occurred after treatment.
    Conclusion: In newly diagnosed older patients with AML whose IACA assessment was unfit or frail for standard chemotherapy, treatment with low-dose decitabine demonstrated clinical activity and good security in our study.
    Keywords:  AML; comprehensive geriatric assessment; elderly; low-dose decitabine; treatment
    DOI:  https://doi.org/10.1177/20406207231208979
  33. Leukemia. 2023 Nov 25.
    Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study.
    Gianantonio Rosti, Tim H Brümmendorf, Björn T Gjertsen, Pilar Giraldo-Castellano, Fausto Castagnetti, Carlo Gambacorti-Passerini, Thomas Ernst, Huadong Zhao, Luke Kuttschreuter, Simon Purcell, Francis J Giles, Andreas Hochhaus.
      In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.
    DOI:  https://doi.org/10.1038/s41375-023-02080-y
  34. Curr Opin Hematol. 2023 Nov 24.
    The future of HOXA-expressing leukemias: Menin inhibitor response and resistance.
    Daniela V Wenge, Scott A Armstrong.
       PURPOSE OF REVIEW: We provide an update on the successes and ongoing challenges of Menin inhibition as a novel approach for the treatment of patients with acute leukemias that express HOXA cluster genes including leukemias with KMT2A-rearrangements, NPM1 mutations or NUP98-rearrangements. Initial clinical trials show promising response rates in heavily pretreated patients suggesting these inhibitors may have a significant impact on patient outcome. Furthermore, the development of resistance mutations that decrease drug binding affinity, validates Menin as a therapeutic target in human cancers. Therapeutic strategies aiming at overcoming and preventing resistance, are of high clinical relevance.
    RECENT FINDINGS: Several Menin inhibitor chemotypes have entered clinical trials. Acquired point mutations have recently been described as a mechanism of resistance towards Menin inhibitors. However, resistance can develop in absence of these mutations. Combination therapies are currently being investigated in preclinical models and in early phase clinical trials.
    SUMMARY: Given the remarkable overall response rates, shedding light on treatment options for patients whose leukemias develop resistance to Menin inhibitors is an imminent clinical need. Studying the underlying mechanisms to inform clinical decision making, and to potentially prevent the development of resistance is of outmost importance.
    DOI:  https://doi.org/10.1097/MOH.0000000000000796
  35. Biochim Biophys Acta Gene Regul Mech. 2023 Nov 25. pii: S1874-9399(23)00099-8. [Epub ahead of print]1867(1): 195004
    Insight into the mechanism of AML del(9q) progression: hnRNP K targets the myeloid master regulators CEBPA (C/EBPα) and SPI1 (PU.1).
    Kerstin Rahn, Ali T Abdallah, Lin Gan, Shelley Herbrich, Roland Sonntag, Oscar Benitez, Prerna Malaney, Xiaorui Zhang, Ashely G Rodriguez, Jared Brottem, Gernot Marx, Tim H Brümmendorf, Dirk H Ostareck, Antje Ostareck-Lederer, Martina Crysandt, Sean M Post, Isabel S Naarmann-de Vries.
      Deletions on the long arm of chromosome 9 (del(9q)) are recurrent abnormalities in about 2 % of acute myeloid leukemia cases, which usually involve HNRNPK and are frequently associated with other known aberrations. Based on an Hnrnpk haploinsufficient mouse model, a recent study demonstrated a function of hnRNP K in pathogenesis of myeloid malignancies via the regulation of cellular proliferation and myeloid differentiation programs. Here, we provide evidence that reduced hnRNP K expression results in the dysregulated expression of C/EBPα and additional transcription factors. CyTOF analysis revealed monocytic skewing with increased levels of mature myeloid cells. To explore the role of hnRNP K during normal and pathological myeloid differentiation in humans, we characterized hnRNP K-interacting RNAs in human AML cell lines. Notably, RNA-sequencing revealed several mRNAs encoding key transcription factors involved in the regulation of myeloid differentiation as targets of hnRNP K. We showed that specific sequence motifs confer the interaction of SPI1 and CEBPA 5' and 3'UTRs with hnRNP K. The siRNA mediated reduction of hnRNP K in human AML cells resulted in an increase of PU.1 and C/EBPα that is most pronounced for the p30 isoform. The combinatorial treatment with the inducer of myeloid differentiation valproic acid resulted in increased C/EBPα expression and myeloid differentiation. Together, our results indicate that hnRNP K post-transcriptionally regulates the expression of myeloid master transcription factors. These novel findings can inaugurate novel options for targeted treatment of AML del(9q) by modulation of hnRNP K function.
    Keywords:  AML; CEBPA; HNRNPK; SPI1; del(9q)
    DOI:  https://doi.org/10.1016/j.bbagrm.2023.195004
  36. Nat Commun. 2023 Nov 28. 14(1): 7464
    Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens.
    Shaela Wright, Xujie Zhao, Wojciech Rosikiewicz, Shelby Mryncza, Judith Hyle, Wenjie Qi, Zhenling Liu, Siqi Yi, Yong Cheng, Beisi Xu, Chunliang Li.
      Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.
    DOI:  https://doi.org/10.1038/s41467-023-43264-5
  37. Methods Mol Biol. 2024 ;2747 211-227
    Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow.
    Floriane S Tissot, Sara Gonzalez-Anton, Cristina Lo Celso.
      Hematopoiesis is the process through which all mature blood cells are formed and takes place in the bone marrow (BM). Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. AML progression causes drastic remodeling of the BM microenvironment, making it no longer supportive of healthy hematopoiesis and leading to clinical cytopenia in patients. Understanding the mechanisms by which AML cells shape the BM to their benefit would lead to the development of new therapeutic strategies. While the role of extracellular matrix (ECM) in solid cancer has been extensively studied during decades, its role in the BM and in leukemia progression has only begun to be acknowledged. In this context, intravital microscopy (IVM) gives the unique insight of direct in vivo observation of AML cell behavior in their environment during disease progression and/or upon drug treatments. Here we describe our protocol for visualizing and analyzing MLL-AF9 AML cell dynamics upon systemic inhibition of matrix metalloproteinases (MMP), combining confocal and two-photon microscopy and focusing on cell migration.
    Keywords:  Bone marrow; Bone marrow microenvironment; Cell migration; Extracellular matrix; Intravital microscopy; Leukemia; Matrix metalloproteinase
    DOI:  https://doi.org/10.1007/978-1-0716-3589-6_17
  38. bioRxiv. 2023 Nov 15. pii: 2023.11.11.566719. [Epub ahead of print]
    Deep generative model deciphers derailed trajectories in acute myeloid leukemia.
    Achille Nazaret, Joy Linyue Fan, Vincent-Philippe Lavallée, Andrew E Cornish, Vaidotas Kiseliovas, Ignas Masilionis, Jaeyoung Chun, Robert L Bowman, Shira E Eisman, James Wang, Lingting Shi, Ross L Levine, Linas Mazutis, David Blei, Dana Pe'er, Elham Azizi.
      Single-cell genomics has the potential to map cell states and their dynamics in an unbiased way in response to perturbations like disease. However, elucidating the cell-state transitions from healthy to disease requires analyzing data from perturbed samples jointly with unperturbed reference samples. Existing methods for integrating and jointly visualizing single-cell datasets from distinct contexts tend to remove key biological differences or do not correctly harmonize shared mechanisms. We present Decipher, a model that combines variational autoencoders with deep exponential families to reconstruct derailed trajectories ( https://github.com/azizilab/decipher ). Decipher jointly represents normal and perturbed single-cell RNA-seq datasets, revealing shared and disrupted dynamics. It further introduces a novel approach to visualize data, without the need for methods such as UMAP or TSNE. We demonstrate Decipher on data from acute myeloid leukemia patient bone marrow specimens, showing that it successfully characterizes the divergence from normal hematopoiesis and identifies transcriptional programs that become disrupted in each patient when they acquire NPM1 driver mutations.
    DOI:  https://doi.org/10.1101/2023.11.11.566719
  39. Ann Hematol. 2023 Dec 01.
    A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents.
    Jan Philipp Bewersdorf, Rory M Shallis, Elad Sharon, Silvia Park, Rahul Ramaswamy, Caroline E Roe, Jonathan M Irish, Anne Caldwell, Wei Wei, Abdulraheem Yacoub, Yazan F Madanat, Joshua F Zeidner, Jessica K Altman, Olatoyosi Odenike, Swaroopa Yerrabothala, Tibor Kovacsovics, Nikolai A Podoltsev, Stephanie Halene, Richard F Little, Richard Piekarz, Steven D Gore, Tae Kon Kim, Amer M Zeidan.
      Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.
    Keywords:  AML; Entinostat; MDS; Myeloid-derived suppressor cells; Pembrolizumab
    DOI:  https://doi.org/10.1007/s00277-023-05552-4
  40. Br J Haematol. 2023 Nov 27.
    Characterization of a novel IDH2-R159H mutation in acute myeloid leukaemia: Effects on cell metabolism and differentiation.
    Anna Maria Nardozza, Luca Guarnera, Serena Travaglini, Tiziana Ottone, Mariadomenica Divona, Eleonora De Bellis, Arianna Savi, Cristina Banella, Nelida Ines Noguera, Davide Di Fusco, Ivan Monteleone, Maria Teresa Voso.
      
    DOI:  https://doi.org/10.1111/bjh.19216
  41. Haematologica. 2023 Dec 01. 108(12): 3191-3192
    Clonal evolution of leukemia from G6PD studies.
    Tal Bacharach, Liran I Shlush.
      
    DOI:  https://doi.org/10.3324/haematol.2023.284215
  42. Exp Hematol. 2023 Nov 28. pii: S0301-472X(23)01770-8. [Epub ahead of print]
    Understanding Genetic Heterogeneity in Gene-Edited HSC Products.
    Hans Jiro Becker, Satoshi Yamazaki.
      CRISPR/Cas gene editing has transformed genetic research and is poised to drive the next generation of gene therapies targeting hematopoietic stem cells (HSCs). However, the installation of the 'desired' edit is most often only achieved in a minor subset of alleles. The array of cellular pathways triggered by gene editing tools produces a broad spectrum of 'undesired' editing outcomes, including short insertions and deletions (indels) and chromosome rearrangements, leading to considerable genetic heterogeneity in gene edited HSC populations. This heterogeneity may undermine the effect of the genetic intervention, since only a subset of cells will carry the intended modification. Also, undesired mutations represent a potential safety concern as gene editing advances toward broader clinical use. Here, we will review the different sources of 'undesired' edits and will discuss strategies for their mitigation and control.
    DOI:  https://doi.org/10.1016/j.exphem.2023.11.007
  43. Br J Haematol. 2023 Nov 27.
    Characteristics and long-term outcome in a large series of chronic myelomonocytic leukaemia patients including 104 formerly referred to as oligomonocytic.
    Sandra Castaño-Díez, Helena Pomares, Daniel Esteban, Francesca Guijarro, Carlos Jiménez-Vicente, Inés Zugasti, José Ramón Álamo, Víctor Torrecillas Mayayo, Mònica López-Guerra, Cristina de la Fuente, Paola Charry, Albert Cortés-Bullich, Álex Bataller, Clara Maluquer, Dolors Colomer, María Rozman, Montserrat Arnan, Blanca Xicoy, Jordi Esteve, Marina Díaz-Beyá.
      Recently modified diagnostic criteria for chronic myelomonocytic leukaemia (CMML) have lowered the cut-off for absolute monocytosis. In the largest series to date, we have analysed 313 CMML patients, including 104 with oligomonocytic (OM)-CMML. Five-year survival was longer for OM-CMML than for other patients (p < 0.001). Multivariate analysis identified OM-CMML as a favourable prognostic factor (HR 0.58; p = 0.002). The 5-year cumulative incidence of progression to classical CMML was 47%. Older age and transfusion dependence were adverse prognostic factors for OM-CMML. Our results support the inclusion of OM-CMML in the CMML category as a subtype with superior outcomes.
    Keywords:  CMML; chronic myelomonocytic leukaemia; oligomonocytic
    DOI:  https://doi.org/10.1111/bjh.19217
  44. Hemasphere. 2023 Dec;7(12): e978
    CK2β Regulates Hematopoietic Stem Cell Biology and Erythropoiesis.
    Laura Quotti Tubi, Sara Canovas Nunes, Elisa Mandato, Marco Pizzi, Nicola Vitulo, Mirco D'Agnolo, Raffaella Colombatti, Maddalena Martella, Maria Paola Boaro, Elena Doriguzzi Breatta, Anna Fregnani, Zaira Spinello, Mitja Nabergoj, Odile Filhol, Brigitte Boldyreff, Mattia Albiero, Gian Paolo Fadini, Carmela Gurrieri, Fabrizio Vianello, Gianpietro Semenzato, Sabrina Manni, Livio Trentin, Francesco Piazza.
      The Ser-Thr kinase CK2 plays important roles in sustaining cell survival and resistance to stress and these functions are exploited by different types of blood tumors. Yet, the physiological involvement of CK2 in normal blood cell development is poorly known. Here, we discovered that the β regulatory subunit of CK2 is critical for normal hematopoiesis in the mouse. Fetal livers of conditional CK2β knockout embryos showed increased numbers of hematopoietic stem cells associated to a higher proliferation rate compared to control animals. Both hematopoietic stem and progenitor cells (HSPCs) displayed alterations in the expression of transcription factors involved in cell quiescence, self-renewal, and lineage commitment. HSPCs lacking CK2β were functionally impaired in supporting both in vitro and in vivo hematopoiesis as demonstrated by transplantation assays. Furthermore, KO mice developed anemia due to a reduced number of mature erythroid cells. This compartment was characterized by dysplasia, proliferative defects at early precursor stage, and apoptosis at late-stage erythroblasts. Erythroid cells exhibited a marked compromise of signaling cascades downstream of the cKit and erythropoietin receptor, with a defective activation of ERK/JNK, JAK/STAT5, and PI3K/AKT pathways and perturbations of several transcriptional programs as demonstrated by RNA-Seq analysis. Moreover, we unraveled an unforeseen molecular mechanism whereby CK2 sustains GATA1 stability and transcriptional proficiency. Thus, our work demonstrates new and crucial functions of CK2 in HSPC biology and in erythropoiesis.
    DOI:  https://doi.org/10.1097/HS9.0000000000000978
  45. Sci Adv. 2023 Dec;9(48): eadi7375
    ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS.
    Jia-Cheng Jin, Bing-Yi Chen, Chu-Han Deng, Jia-Nan Chen, Feng Xu, Ying Tao, Cheng-Long Hu, Chun-Hui Xu, Bin-He Chang, Yong Wang, Ming-Yue Fei, Ping Liu, Peng-Cheng Yu, Zi-Juan Li, Xi-Ya Li, Shu-Bei Chen, Yi-Lun Jiang, Xin-Chi Chen, Li-Juan Zong, Jia-Ying Zhang, Yi-Yi Ren, Fan-Huan Xu, Qi Liu, Xin-Hui Huang, Juan Guo, Qi He, Lu-Xi Song, Li-Yu Zhou, Ji-Ying Su, Chao Xiao, Yu-Mei Zhang, Meng Yan, Zheng Zhang, Dong Wu, Chun-Kang Chang, Xiao Li, Lan Wang, Ling-Yun Wu.
      Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.
    DOI:  https://doi.org/10.1126/sciadv.adi7375
  46. Leukemia. 2023 Nov 28.
    SRSF2 mutation cooperates with ASXL1 truncated alteration to accelerate leukemogenesis.
    Pinpin Sui, Guo Ge, Shi Chen, Jiaojiao Bai, Ivan P Rubalcava, Hui Yang, Ying Guo, Peng Zhang, Ying Li, Edward A Medina, Mingjiang Xu, Omar Abdel-Wahab, Robert Bradley, Feng-Chun Yang.
      
    DOI:  https://doi.org/10.1038/s41375-023-02094-6
  47. Hemasphere. 2023 Dec;7(12): e981
    Prognostic Significance of Measurable Residual Disease Detection by Flow Cytometry in Autologous Stem Cell Apheresis Products in AML.
    Jesse M Tettero, Yara Buisman, Lok Lam Ngai, Costa Bachas, Bjorn T Gjertsen, Angèle Kelder, Arjan A van de Loosdrecht, Markus G Manz, Thomas Pabst, Willemijn Scholten, Gert J Ossenkoppele, Jacqueline Cloos, David C de Leeuw.
      
    DOI:  https://doi.org/10.1097/HS9.0000000000000981
  48. Br J Haematol. 2023 Nov 28.
    Pathogenic DDX41 variants, possible response predictors to low-dose melphalan in hypo- and normocellular MDS and AML.
    Otto Emil Nyquist, Jakob Dalgaard, Signe Spetalen, Synne Torkildsen, Hege Frøen, Eivind Galteland, Ole Klungsøyr, Astrid Bergrem, Camilla Vo, Hjalmar Sørbø, Birgitte Eiken, Hedda Lerdal, Ann-Karin Solvang, Hilde Jensvoll, Tatjana Pandzic, Panagiotis Baliakas, Ingunn Dybedal.
      
    DOI:  https://doi.org/10.1111/bjh.19226
  49. Nat Genet. 2023 Nov 30.
    The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells.
    Gene Ching Chiek Koh, Soraya Boushaki, Salome Jingchen Zhao, Andrew Marcel Pregnall, Firas Sadiyah, Cherif Badja, Yasin Memari, Ilias Georgakopoulos-Soares, Serena Nik-Zainal.
      The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1-, BRCA2- and PALB2-mutated cancers. It is under investigation in phase I and II trials. Here, we find that, although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, nonselective, collateral mutagenesis in all three cell lines tested, to magnitudes that exceed known environmental carcinogens.
    DOI:  https://doi.org/10.1038/s41588-023-01602-9
  50. Am J Hematol. 2023 Nov 27.
    Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS-a study of the CMWP of the EBMT.
    Alicia Rovó, Luuk Gras, Brian Piepenbroek, Nicolaus Kröger, H Christian Reinhardt, Aleksandar Radujkovic, Didier Blaise, Guido Kobbe, Riitta Niityvuopio, Uwe Platzbecker, Katja Sockel, Mathilde Hunault-Berger, J J Cornelissen, Edouard Forcade, Jean Henri Bourhis, Yves Chalandon, Francesca Kinsella, Stéphanie Nguyen-Quoc, Johan Maertens, Ahmet Elmaagacli, Nicola Mordini, Patrick Hayden, Kavita Raj, Joanna Drozd-Sokolowska, Liesbeth C de Wreede, Donal P McLornan, Marie Robin, Ibrahim Yakoub-Agha, Francesco Onida.
      Although CMML since long has been separated from MDS, many studies continue to evaluate the outcomes of both diseases after hematopoietic cell transplantation (allo-HCT) together. Data evaluating outcomes of a large CMML cohort after allo-HCT compared to MDS are limited. We aim to compare outcomes of CMML to MDS patients who underwent allo-HCT between 2010 and 2018. Patients ≥18 years with CMML and MDS undergoing allo-HCT reported to the EBMT registry were analyzed. Progression to AML before allo-HCT was an exclusion criterion. Overall survival (OS), progression/relapse-free survival (PFS), relapse incidence (including progression) (REL), and non-relapse mortality (NRM) were evaluated in univariable and multivariable (MVA) Cox proportional hazard models including interaction terms between disease and confounders. In total, 10832 patients who underwent allo-HCT were included in the study, there were a total of 1466 CMML, and 9366 MDS. The median age at time of allo-HCT in CMML (median 60.5, IQR 54.3-65.2 years) was significantly higher than in the MDS cohort (median 58.8, IQR 50.2-64.5 years; p < .001). A significantly higher percentage of CMML patients were male (69.4%) compared to MDS (61.2%; p < .001). There were no clinically meaningful differences in the distribution of Karnofsky score, Sorror HCT-CI score at allo-HCT, and donor type, between the CMML and MDS patients. RIC platforms were utilized in 63.9% of CMML allo-HCT, and in 61.4% of MDS patients (p = .08). In univariable analyses, we found that OS, PFS, and REL were significantly worse in CMML when compared with MDS (all p < .0001), whereas no significant difference was observed in NRM (p = .77). In multivariable analyses, the HR comparing MDS versus CMML for OS was 0.81 (95% CI, 0.74-0.88, p < .001), PFS 0.76 (95% CI 0.70-0.82, p < .001), relapse 0.66 (95% CI 0.59-0.74, p < .001), and NRM 0.87 (95% CI 0.78-0.98, p = .02), respectively. The association between baseline variables and outcome was found to be similar in MDS and CMML (all interaction p > .05) except for a decreasing trend over time of the risk of relapse in CMML (HR allo-HCT per year later 0.94, 95% CI 0.90-0.98), whereas no such trend was observed in MDS (HR 1.00, 95% CI 0.98-1.02). The poor outcome observed for CMML could be related to variables not measured in this study or to factors inherent to the disease itself. This study demonstrates that outcomes of CMML patients after allo-HCT are significantly worse compared to MDS. The results of this study may contribute to future recommendations for allo-HCT in CMML patients.
    DOI:  https://doi.org/10.1002/ajh.27150
  51. Hemasphere. 2023 Dec;7(12): e979
    Integration of Transcriptomic Features to Improve Prognosis Prediction of Pediatric Acute Myeloid Leukemia With KMT2A Rearrangement.
    Jun Li, Suyu Zong, Yang Wan, Min Ruan, Li Zhang, Wenyu Yang, Xiaojuan Chen, Yao Zou, Yumei Chen, Ye Guo, Peng Wu, Yingchi Zhang, Xiaofan Zhu.
      Lysine methyltransferase 2A-rearranged acute myeloid leukemia (KMT2A-r AML) is a special entity in the 2022 World Health Organization classification of myeloid neoplasms, characterized by high relapse rate and adverse outcomes. Current risk stratification was established on the treatment response and translocation partner of KMT2A. To study the transcriptomic feature and refine the current stratification of pediatric KMT2A-r AML, we analyzed clinical and RNA sequencing data of 351 patients. By implementing least absolute shrinkage and selection operator algorithm, we identified 7 genes (KIAA1522, SKAP2, EGFL7, GAB2, HEBP1, FAM174B, and STARD8) of which the expression levels were strongly associated with outcomes. We then developed a transcriptome-based score, dividing patients into 2 groups with distinct gene expression patterns and prognosis, which was further validated in an independent cohort and outperformed the LSC17 score. We also found cell cycle, oxidative phosphorylation, and metabolism pathways were upregulated in patients with inferior outcomes. By integrating clinical characteristics, we proposed a simple-to-use prognostic scoring system with excellent discriminability, which allowed us to distinguish allogeneic hematopoietic stem cell transplantation candidates more precisely. In conclusion, pediatric KMT2A-r AML is heterogenous on transcriptomic level and the newly proposed scoring system combining clinical characteristics and transcriptomic features can be instructive in clinical routines.
    DOI:  https://doi.org/10.1097/HS9.0000000000000979
  52. EJHaem. 2023 Nov;4(4): 1105-1109
    Persistence of UBTF tandem duplications in remission in acute myeloid leukaemia.
    Sean Harrop, Phillip C Nguyen, David Byrne, Clarissa Wilson, Georgina L Ryland, Tamia Nguyen, Mary Ann Anderson, Seong Lin Khaw, Michelle Martin, Ing Soo Tiong, Elaine Sanij, Piers Blombery.
      UBTF tandem duplications are recurrent in adult and paediatric acute myeloid leukaemia and have been reported to be associated with a poor prognosis. Co-mutations in WT1 and FLT3 are common while morphological dysplasia is frequent. The role of UBTF-TDs in leukemogenesis is yet to be elucidated; however they have been proposed as early initiating events, making them attractive for assessment of MRD and a potential therapeutic target. We present two cases where the UBTF-TD was observed in remission and discuss the implications of these findings in the clinicobiological understanding of this emerging entity.
    Keywords:  acute leukaemia; cancer genetics; molecular
    DOI:  https://doi.org/10.1002/jha2.808
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