bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024‒04‒21
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer.
  2. Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.
  3. Exploring the landscape of somatic ASXL2 mutations in myeloid neoplasms: Frequency and clinical implications.
  4. Post-transplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil compared to anti-thymocyte globulin, calcineurin inhibitor, and methotrexate combinations as graft-versus-host disease prophylaxis post allogeneic stem cell transplantation from sibling and unrelated donors in patients with acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
  5. Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia.
  6. The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.
  7. Cutaneous clonal mature plasmacytoid dendritic cell dermatosis in patients with myeloid neoplasms.
  8. Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.
  9. Molecular responses in decitabine- and decitabine/venetoclax-treated patients with acute myeloid leukemia and myelodysplastic syndromes.
  10. Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.
  11. Optimized Cytogenetic Risk-Group Stratification of KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.
  12. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with BCR::ABL1 fusion.
  13. How lipid coating soothes the gut in AML therapy.
  14. Final phase I substudy results of ivosidenib in patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome.
  15. Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody.
  16. Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms.
  17. Germline assessment for alloHSCT candidates over 50 years: A 'Fast-Track' screening in myeloid neoplasms.
  18. Ascorbate depletion increases quiescence and self-renewal potential in hematopoietic stem cells and multipotent progenitors.
  19. RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells.
  20. Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia.
  21. Lysosomal Degradation Targets Mutant Calreticulin and the Thrombopoietin Receptor in Myeloproliferative Neoplasms.
  22. Recipient clonal hematopoiesis in allogeneic bone marrow transplantation for lymphoid malignancies.
  23. Somatic epimutations enable single-cell lineage tracing in native hematopoiesis across the murine and human lifespan.
  24. Combination therapies with ponatinib and asciminib in a preclinical model of chronic myeloid leukemia blast crisis with compound mutations.
  25. Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma.
  26. Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055.
  27. Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer.
  28. A practical algorithm for acute myeloid leukaemia diagnosis following the updated 2022 classifications.
  29. Caspase 8 deletion causes infection/inflammation-induced bone marrow failure and MDS-like disease in mice.
  30. Validation of mutated CEBPA bZIP as a distinct prognosis entity in acute myeloid leukemia: a study by the Spanish PETHEMA registry.
  31. Measurable residual disease (MRD)-testing in haematological and solid cancers.
  32. Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.
  33. Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.
  1. Leukemia. 2024 Apr 18.
    Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer.
    Christopher Maximilian Arends, Klara Kopp, Raphael Hablesreiter, Natalia Estrada, Friederike Christen, Ute Martha Moll, Robert Zeillinger, Wolfgang Daniel Schmitt, Jalid Sehouli, Hagen Kulbe, Maximilian Fleischmann, Isabelle Ray-Coquard, Alain Zeimet, Francesco Raspagliesi, Claudio Zamagni, Ignace Vergote, Domenica Lorusso, Nicole Concin, Lars Bullinger, Elena Ioana Braicu, Frederik Damm.
      Clonal hematopoiesis (CH) driven by mutations in the DNA damage response (DDR) pathway is frequent in patients with cancer and is associated with a higher risk of therapy-related myeloid neoplasms (t-MNs). Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes. DDR-driven CH was detected in 35% of patients and was associated with longer duration of prior PARPi treatment. TP53- and PPM1D-mutated clones exhibited substantially higher clonal expansion rates than DNMT3A- or TET2-mutated clones during treatment. Expansion of DDR clones correlated with HSP90i exposure across the three study arms and was partially abrogated by the presence of germline mutations related to homologous recombination deficiency. Single-cell DNA sequencing of selected samples revealed clonal exclusivity of DDR mutations, and identified DDR-mutated clones as the origin of t-MN in two investigated cases. Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.
    DOI:  https://doi.org/10.1038/s41375-024-02253-3
  2. Ann Hematol. 2024 Apr 17.
    Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.
    Daniel Zechariah Paul Jebanesan, Raveen Stephen Stallon Illangeswaran, Bharathi M Rajamani, Rakhi Thalayattu Vidhyadharan, Saswati Das, Nayanthara K Bijukumar, Balaji Balakrishnan, Vikram Mathews, Shaji R Velayudhan, Poonkuzhali Balasubramanian.
      De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples. We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2 expression, nuclear localization, and upregulation of bonafide NRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.
    Keywords:  AML; Acquired chemoresistance; Arsenic trioxide; Digoxin; FLT3-ITD; NRF2
    DOI:  https://doi.org/10.1007/s00277-024-05742-8
  3. Am J Hematol. 2024 Apr 13.
    Exploring the landscape of somatic ASXL2 mutations in myeloid neoplasms: Frequency and clinical implications.
    Tareq Abuasab, Gautam Borthakur, Rashmi Kanagal-Shamanna, Lucia Masarova, Keyur Patel, Koichi Takahashi, Prithviraj Bose, John Villarreal, Sherry Pierce, Tapan Kadia, Guillermo Garcia-Manero, Nicholas J Short, Courtney DiNardo, Naval Daver, Farhad Ravandi, Hagop Kantarjian, Srdan Verstovsek, Musa Yilmaz.
      
    DOI:  https://doi.org/10.1002/ajh.27333
  4. Bone Marrow Transplant. 2024 Apr 13.
    Post-transplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil compared to anti-thymocyte globulin, calcineurin inhibitor, and methotrexate combinations as graft-versus-host disease prophylaxis post allogeneic stem cell transplantation from sibling and unrelated donors in patients with acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
    Arnon Nagler, Myriam Labopin, Ryszard Swoboda, Thomas Schroeder, Rose-Marie Hamladji, Laimonas Griskevicius, Urpu Salmenniemi, Alessandro Rambaldi, Stephan Mielke, Alexander Kulagin, Jakob Passweg, Thomas Luft, Tobias Gedde-Dahl, Edouard Forcade, Grzegorz Helbig, Matthias Stelljes, Cristina Castilla-Llorente, Alexandros Spyridonidis, Eolia Brissot, Fabio Ciceri, Mohamad Mohty.
      Post-transplant cyclophosphamide plus calcineurin inhibitor (CNI)(tacrolimus or cyclosporine A) plus mycophenolate mofetil (PTCy/TAC or CSA/MMF) and anti-thymocyte globulin plus CNI (tacrolimus or cyclosporine A) plus methotrexate (ATG/TAC or CSA/MTX) are common graft-versus-host disease (GVHD) prophylaxis regimens. We compared the two regimens in patients with acute myeloid leukemia (AML) undergoing allogeneic transplantation from matched siblings or unrelated donors. 402 received PTCy/TAC or CSA/MMF and 5648 received ATG/TAC or CSA/MTX. Patients in the PTCy-based group were younger (48.7 vs. 51.5 years, p = 0.024) and there was a higher frequency of patient cytomegalovirus seropositivity and female donor to male patient combination in this group (77.8% vs. 71.8%, p = 0.009 and 18.4% vs. 14.4%, p = 0.029, respectively). More patients in the PTCy-based group received reduced-intensity conditioning (51.5% vs. 41%, p < 0.0001). No differences were observed in the incidence of acute GVHD grade II-IV and III-IV (21.2% vs. 20.4%, p = 0.92 and 8.1% vs. 6%, p = 0.1) or 2-year total and extensive chronic GVHD (33.7% vs. 30%, p = 0.09 and 10.7% vs. 11.2%, p = 0.81) between the groups. In the multivariate analysis, all transplant outcomes did not differ between the groups. PTCy/CNI/MMF and ATG/CNI/MTX are alternative regimens for GVHD prophylaxis in AML patients.
    DOI:  https://doi.org/10.1038/s41409-024-02284-5
  5. Clin Cancer Res. 2024 Apr 15. OF1-OF13
    Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia.
    Guangrong Qin, Jin Dai, Sylvia Chien, Timothy J Martins, Brenda Loera, Quy H Nguyen, Melanie L Oakes, Bahar Tercan, Boris Aguilar, Lauren Hagen, Jeannine McCune, Richard Gelinas, Raymond J Monnat, Ilya Shmulevich, Pamela S Becker.
      PURPOSE: The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community.EXPERIMENTAL DESIGN: We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML. Statistical approaches and machine learning models were applied to identify signatures for drug response prediction. We also integrated large public datasets to understand the co-occurring mutation patterns and further investigated the mutation profiles in the single cells. The features revealed in the co-occurring or mutual exclusivity pattern were further subjected to machine learning models.
    RESULTS: We detected genetic signatures associated with sensitivity or resistance to specific agents, and identified five co-occurring mutation groups. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct subclones within patients with AML. Using the mutation pattern for drug response prediction demonstrates high accuracy in predicting sensitivity to some drug classes, such as MEK inhibitors for RAS-mutated leukemia.
    CONCLUSIONS: Our study highlights the importance of considering the gene mutation patterns for the prediction of drug response in AML. It provides a framework for categorizing patients with AML by mutations that enable drug sensitivity prediction.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1674
  6. Nat Cancer. 2024 Apr 18.
    The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.
    Hannah Lawson, James P Holt-Martyn, Vilma Dembitz, Yuka Kabayama, Lydia M Wang, Aarushi Bellani, Samanpreet Atwal, Nadia Saffoon, Jozef Durko, Louie N van de Lagemaat, Azzura L De Pace, Anthony Tumber, Thomas Corner, Eidarus Salah, Christine Arndt, Lennart Brewitz, Matthew Bowen, Louis Dubusse, Derek George, Lewis Allen, Amelie V Guitart, Tsz Kan Fung, Chi Wai Eric So, Juerg Schwaller, Paolo Gallipoli, Donal O'Carroll, Christopher J Schofield, Kamil R Kranc.
      Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.
    DOI:  https://doi.org/10.1038/s43018-024-00761-w
  7. Blood Adv. 2024 Apr 12. pii: bloodadvances.2023012489. [Epub ahead of print]
    Cutaneous clonal mature plasmacytoid dendritic cell dermatosis in patients with myeloid neoplasms.
    Thibault Mahévas, Amélie Osio, Lise Larcher, Emmanuelle Clappier, Werner Kempf, Lionel Adès, Pierre Fenaux, Marie Sébert, Jérémie Delaleu, Marie Jachiet, Florence Cordoliani, Estelle Charvet, Olivier Carpentier, Raphaël A Itzykson, Marie Weinborn, Nicoleta Mardare, Joséfina Marco-Bonnet, Adèle de Masson, Nicolas Duployez, Tony Huynh, Jean-David Bouaziz, Marie-Dominique Vignon-Pennamen, Maxime Battistella.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023012489
  8. iScience. 2024 Apr 19. 27(4): 109576
    Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.
    Daniel J L Coleman, Peter Keane, Paulynn S Chin, Luke Ames, Sophie Kellaway, Helen Blair, Naeem Khan, James Griffin, Elizabeth Holmes, Alexander Maytum, Sandeep Potluri, Lara Strate, Kinga Koscielniak, Manoj Raghavan, John Bushweller, Olaf Heidenreich, Terry Rabbitts, Peter N Cockerill, Constanze Bonifer.
      AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.
    Keywords:  Molecular biology; Pharmacy
    DOI:  https://doi.org/10.1016/j.isci.2024.109576
  9. Haematologica. 2024 Apr 11.
    Molecular responses in decitabine- and decitabine/venetoclax-treated patients with acute myeloid leukemia and myelodysplastic syndromes.
    Agata Gruszczynska, Abhishek Maiti, Christopher A Miller, Sai Mukund Ramakrishnan, Daniel C Link, Geoffrey L Uy, Allegra A Petti, Kala Hayes, Courtney D DiNardo, Farhad Ravandi, Timothy J Ley, David H Spencer, Feng Gao, Marina Y Konopleva, John S Welch.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.281396
  10. Leuk Res. 2024 Apr 15. pii: S0145-2126(24)00066-3. [Epub ahead of print]141 107500
    Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.
    Guillaume Berton, Bochra Sedaki, Erwann Collomb, Sami Benachour, Michael Loschi, Bilal Mohty, Colombe Saillard, Yosr Hicheri, Camille Rouzaud, Valerio Maisano, Ferdinand Villetard, Evelyne D 'Incan Corda, Aude Charbonnier, Jerome Rey, Marie-Anne Hospital, Antoine Ittel, Norman Abbou, Raphaelle Fanciullino, Bérengère Dadone-Montaudié, Norbert Vey, Geoffroy Venton, Thomas Cluzeau, Anne-Sophie Alary, Sylvain Garciaz.
      Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.
    Keywords:  AML; BCL-2; Molecular Biology; Prognostic factors
    DOI:  https://doi.org/10.1016/j.leukres.2024.107500
  11. Blood Adv. 2024 Apr 15. pii: bloodadvances.2023011771. [Epub ahead of print]
    Optimized Cytogenetic Risk-Group Stratification of KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.
    Romy Elise van Weelderen, Christine J Harrison, Kim Klein, Yilin Jiang, Jonas Abrahamsson, Todd Alonzo, Richard Aplenc, Nira Arad-Cohen, Emmanuelle Bart-Delabesse, Barbara Buldini, Barbara De Moerloose, Michael N Dworzak, Sarah Elitzur, José M Fernández Navarro, Alan S Gamis, Robert B Gerbing, Bianca F Goemans, Hester A de Groot-Kruseman, Erin M Guest, Shau Yin Ha, Henrik Hasle, Charikleia Kelaidi, Helene Lapillonne, Guy Leverger, Franco Locatelli, Takako Miyamura, Ulrika Noren-Nystrom, Sophia Polychronopoulou, Mareike Rasche, Jeffrey E Rubnitz, Jan Stary, Anne Tierens, Daisuke Tomizawa, Michel C Zwaan, Gertjan J L Kaspers.
      Comprehensive international consensus on cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1,256 children with KMT2A-r AML aimed to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs), and secondly, to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared to our previous study, three additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8% to 76.2%; P<0.01). ACAs occurred in 46.8% of 1,200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P<0.01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcome was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate the five adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcome, and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011771
  12. EJHaem. 2024 Apr;5(2): 369-378
    Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with BCR::ABL1 fusion.
    Shohei Mizuno, Akiyoshi Takami, Koji Kawamura, Kaito Harada, Masuko Masayoshi, Shingo Yano, Ayumu Ito, Yukiyasu Ozawa, Fumihiko Ouchi, Takashi Ashida, Yuichiro Nawa, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Masamitsu Yanada.
      BCR::ABL1 fusion is found in < 1% of de novo acute myeloid leukemia (AML) cases and confers a poor prognosis. This Japanese nationwide survey analyzed patients with AML (n = 22) and mixed phenotype acute leukemia (MPAL) (n = 10) with t(9;22) or BCR::ABL1 who underwent allogeneic hematopoietic cell transplantation (allo-HCT) between 2002 and 2018. The 3-year overall survival (OS) rates were 81.3% and 56.0%, respectively (p = 0.15), and leukemia-free survival (LFS) rates were 76.2% and 42.0%, respectively (p = 0.10) in patients with AML and MPAL. The relapse rates were 9.5% and 14.0% (p = 0.93), and the non-relapse mortality (NRM) rates were 14.3% and 44.0%, respectively (p = 0.10) in patients with AML and MPAL. One in 17 patients with AML, with pre-transplant tyrosine kinase inhibitors (TKI), and three in five patients with AML, without pre-transplant TKI, did not achieve complete remission (CR) before allo-HCT (p = 0.024). Among the 20 patients with known disease status after allo-HCT, 95.0% were in hematological or molecular CR. None of the four patients who received post-transplant TKI for prophylaxis or measurable residual disease relapse experienced hematological relapse. In conclusion, our results suggest that pre-transplant TKI could improve disease status before allo-HCT. Moreover, allo-HCT resulted in high OS, high LFS, low relapse, and low NRM rates in patients with AML with BCR::ABL1.
    Keywords:  BCR::ABL1; acute myeloid leukemia; allogeneic hematopoietic cell transplantation
    DOI:  https://doi.org/10.1002/jha2.877
  13. Blood. 2024 Apr 18. 143(16): 1559-1561
    How lipid coating soothes the gut in AML therapy.
    Renaud Buffet.
      
    DOI:  https://doi.org/10.1182/blood.2024023908
  14. Blood Adv. 2024 Apr 19. pii: bloodadvances.2023012302. [Epub ahead of print]
    Final phase I substudy results of ivosidenib in patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome.
    Courtney D D DiNardo, Gail J Roboz, Justin M Watts, Yazan F Madanat, Gabrielle T Prince, Praneeth Baratam, Stéphane de Botton, Anthony S Stein, James M Foran, Martha L Arellano, David A Sallman, Mohammad Hossain, Dylan M Marchione, Xiaofei Bai, Prapti A Patel, Stephanie M Kapsalis, Guillermo Garcia-Manero, Amir T Fathi.
      Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor and has shown efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in front-line and relapsed/refractory (R/R) mIDH1 AML populations. We report final data from a phase I single-arm substudy (NCT02074839) of patients with R/R mIDH1 MDS following failure of standard-of-care therapies. Oral ivosidenib was taken once daily on days 1-28 in 28-day cycles. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy endpoint was the complete remission + partial remission (CR+PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in eight (42.1%) patients, including a grade 1 QT interval prolongation in one (5.3%) patient and grade 2 differentiation syndrome in two (10.5%) patients. Rates of CR+PR and objective response (CR +PR+marrow CR) were 38.9% (95% confidence interval [CI]: 17.3, 64.3) and 83.3% (95% CI: 58.6, 96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of >=5 years, and a median OS of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC) and platelet transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion >=56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant by data cut-off. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in patients with mIDH1 R/R MDS.
    DOI:  https://doi.org/10.1182/bloodadvances.2023012302
  15. Blood Cancer J. 2024 Apr 18. 14(1): 67
    Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody.
    Sylwia A Stefańczyk, Ilona Hagelstein, Martina S Lutz, Stefanie Müller, Samuel J Holzmayer, Grace Jarjour, Latifa Zekri, Jonas S Heitmann, Helmut R Salih, Melanie Märklin.
      Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML.
    DOI:  https://doi.org/10.1038/s41408-024-01050-6
  16. Leukemia. 2024 Apr 17.
    Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms.
    Susann Winter, Marie Schneider, Uta Oelschlaegel, Giulia Maggioni, Elena Riva, Marco Gabriele Raddi, Sara Bencini, Benedetta Peruzzi, Desmond Choy, Rita Antunes Dos Reis, Esther Güse, Christopher Lischer, Julio Vera, Jessica A Timms, Nicolas Sompairac, Katja Sockel, Antonella Poloni, Antje Tunger, Matteo Giovanni Della Porta, Valeria Santini, Marc Schmitz, Uwe Platzbecker, Shahram Kordasti.
      
    DOI:  https://doi.org/10.1038/s41375-024-02249-z
  17. Br J Haematol. 2024 Apr 19.
    Germline assessment for alloHSCT candidates over 50 years: A 'Fast-Track' screening in myeloid neoplasms.
    GESMD centres
      Patients aged 50 or above diagnosed with myeloid neoplasms (MNs) are typically not candidates for germline testing. However, approximately 8% carry pathogenic germline variants. Allogeneic haematopoietic stem cell transplantation (alloHSCT) remains an option for those aged over 50; neglecting germline testing could mask the risk for relative donor cell-derived MN. We propose a germline-augmented somatic panel (GASP), combining MN predisposition genes with a myeloid somatic panel for timely germline variant identification when initial testing is not indicated. Out of our 133 whole-exome-sequenced MN cases aged over 50 years, 9% had pathogenic/likely variants. GASP detected 92%, compared to 50% with somatic-only panel. Our study highlights the relevance of germline screening in MN, particularly for alloHSCT candidates without established germline-testing recommendations.
    Keywords:  HSC transplantation; genetic testing; germline predisposition; myeloid neoplasms
    DOI:  https://doi.org/10.1111/bjh.19460
  18. bioRxiv. 2024 Apr 02. pii: 2024.04.01.587574. [Epub ahead of print]
    Ascorbate depletion increases quiescence and self-renewal potential in hematopoietic stem cells and multipotent progenitors.
    Stefano Comazzetto, Daniel L Cassidy, Andrew W DeVilbiss, Elise C Jeffery, Bethany R Ottesen, Amanda R Reyes, Sarah Muh, Thomas P Mathews, Brandon Chen, Zhiyu Zhao, Sean J Morrison.
      Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter severely depleted ascorbate from hematopoietic cells. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potential of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate depletion confers MPPs with long-term self-renewal potential.
    Keywords:  bone marrow transplantation; metabolism; quiescence; vitamin C
    DOI:  https://doi.org/10.1101/2024.04.01.587574
  19. Sci Adv. 2024 Apr 19. 10(16): eadi1782
    RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells.
    Shuanghong Zhu, Yingwan Luo, Kongfei Li, Chen Mei, Yuxia Wang, Lingxu Jiang, Wei Wang, Qi Zhang, Wenli Yang, Wei Lang, Xinping Zhou, Lu Wang, Yanling Ren, Liya Ma, Li Ye, Xin Huang, Jianjun Chen, Jie Sun, Hongyan Tong.
      Mutant isocitrate dehydrogenases (IDHs) produce R-2-hydroxyglutarate (R-2HG), which inhibits the growth of most acute myeloid leukemia (AML) cells. Here, we showed that necroptosis, a form of programmed cell death, contributed to the antileukemia activity of R-2HG. Mechanistically, R-2HG competitively inhibited the activity of lysine demethylase 2B (KDM2B), an α-ketoglutarate-dependent dioxygenase. KDM2B inhibition increased histone 3 lysine 4 trimethylation levels and promoted the expression of receptor-interacting protein kinase 1 (RIPK1), which consequently caused necroptosis in AML cells. The expression of RIPK3 was silenced because of DNA methylation in IDH-mutant (mIDH) AML cells, resulting in R-2HG resistance. Decitabine up-regulated RIPK3 expression and repaired endogenous R-2HG-induced necroptosis pathway in mIDH AML cells. Together, R-2HG induced RIPK1-dependent necroptosis via KDM2B inhibition in AML cells. The loss of RIPK3 protected mIDH AML cells from necroptosis. Restoring RIPK3 expression to exert R-2HG's intrinsic antileukemia effect will be a potential therapeutic strategy in patients with AML.
    DOI:  https://doi.org/10.1126/sciadv.adi1782
  20. Leukemia. 2024 Apr 16.
    Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia.
    Nandita Noronha, Chantal Durette, Maxime Cahuzac, Bianca E Silva, Justine Courtois, Juliette Humeau, Allan Sauvat, Marie-Pierre Hardy, Krystel Vincent, Jean-Philippe Laverdure, Joël Lanoix, Frédéric Baron, Pierre Thibault, Claude Perreault, Gregory Ehx.
      The hypomethylating agent 5-azacytidine (AZA) is the first-line treatment for AML patients unfit for intensive chemotherapy. The effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, evidence supporting higher ERE MAPs presentation after AZA treatment is lacking. Therefore, using proteogenomics, we examined the impact of AZA on the repertoire of MAPs and their source transcripts. AZA-treated AML upregulated both CTA and ERE transcripts, but only CTA MAPs were presented at greater levels. Upregulated ERE transcripts triggered innate immune responses against double-stranded RNAs but were degraded by autophagy, and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2. Autophagy inhibition had an additive effect with AZA on AML cell proliferation and survival, increased ERE levels, increased pro-inflammatory responses, and generated immunogenic tumor-specific ERE-derived MAPs. Finally, autophagy was associated with a lower abundance of CD8+ T-cell markers in AML patients expressing high levels of EREs. This work demonstrates that AZA-induced EREs are degraded by autophagy and shows that inhibiting autophagy can improve the immune recognition of AML blasts in treated patients.
    DOI:  https://doi.org/10.1038/s41375-024-02250-6
  21. Blood Adv. 2024 Apr 19. pii: bloodadvances.2023011432. [Epub ahead of print]
    Lysosomal Degradation Targets Mutant Calreticulin and the Thrombopoietin Receptor in Myeloproliferative Neoplasms.
    Amanpreet Kaur, Arunkumar Venkatesan, Malathi Kandarpa, Moshe Talpaz, Malini Raghavan.
      Somatic mutants of calreticulin (CRT) drive myeloproliferative neoplasms (MPNs) via binding to the thrombopoietin receptor (MPL) and aberrant activation of the JAK/STAT pathway. Compared with healthy donors, platelets from MPN patients with CRT mutations display low cell surface MPL. Additionally, co-expression of MPL with an MPN-linked CRT mutant (CRTDel52) reduces cell surface MPL, suggesting that CRTDel52 may induce MPL degradation. We show that lysosomal degradation is relevant to the turnover of CRTDel52 and MPL. Furthermore, CRTDel52 increases the lysosomal localization and degradation of MPL. Mammalian target of rapamycin (mTOR) inhibitors reduce cellular CRTDel52, MPL and secreted CRTDel52 levels, and impair CRTDel52-mediated cell proliferation. mTOR inhibition also reduces colony formation and differentiation of CD34+ cells from MPN patients but not healthy donors. Together, these findings indicate low surface MPL as a biomarker of mutant CRT-mediated MPN and induced degradation of CRTDel52 and MPL as an avenue for therapeutic intervention.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011432
  22. Blood Adv. 2024 Apr 19. pii: bloodadvances.2023011761. [Epub ahead of print]
    Recipient clonal hematopoiesis in allogeneic bone marrow transplantation for lymphoid malignancies.
    Philip Hollingsworth Imus, Sergiu Pasca, Hua-Ling Tsai, Yosra Aljawai, Kenneth R Cooke, Jeremy D Walston, Christopher D Gocke, Ravi Varadhan, Richard J Jones, Lukasz P Gondek.
      Allogeneic blood and marrow transplantation (alloBMT) is increasingly being used in older patients with blood cancer. Aging is associated with an increasing incidence of clonal hematopoiesis (CH). Although the effects of donor CH on alloBMT has been reported, the impact of recipient CH on alloBMT outcomes is unknown. In this retrospective study, alloBMT recipients age 60 and older with lymphoid malignancies were included. Among 97 consecutive patients who received alloBMT between 2017 and 2022, CH was detected in 60 (62%; 95% CI 51-72%). CH was found in 45% (95% CI 28-64%) of patients aged 60-64, 64% (95% CI 44-81%) of patients aged 65-69, and 73% (95% CI 59-87%) in those above 70. Pretransplant CH was associated with worse survival after alloBMT: 3-year overall survival (OS) was 78% (95% CI 65-94%) for patients without CH versus 47% (95% CI 35-63%) for those with CH, [unadjusted HR 3.1 (95%CI 1.4-6.8; P<0.001)]. Non-relapse mortality (NRM) was higher in patients with CH; cumulative incidence of NRM at one-year was 11% (95% CI 1-22%) versus 35% (95% CI 23-48%), [HR 3.4 (95% CI 1.4-8.5), p=0.009]. Among CH patients, worse OS and NRM was associated with CH burden and number of mutations. Recipient CH had no effect on relapse. In conclusion, older patients with CH experience worse outcomes after alloBMT, almost exclusively attributable to increased NRM. CH is a strong, independent predictor of outcomes. Novel strategies to ameliorate the adverse impacts of patient CH on transplant outcomes are being evaluated.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011761
  23. bioRxiv. 2024 Apr 01. pii: 2024.04.01.587514. [Epub ahead of print]
    Somatic epimutations enable single-cell lineage tracing in native hematopoiesis across the murine and human lifespan.
    Michael Scherer, Indranil Singh, Martina Braun, Chelsea Szu-Tu, Michael Kardorff, Julia Rühle, Robert Frömel, Sergi Beneyto-Calabuig, Simon Raffel, Alejo Rodriguez-Fraticelli, Lars Velten.
      Current approaches to lineage tracing of stem cell clones require genetic engineering or rely on sparse somatic DNA variants, which are difficult to capture at single-cell resolution. Here, we show that targeted single-cell measurements of DNA methylation at single-CpG resolution deliver joint information about cellular differentiation state and clonal identities. We develop EPI-clone, a droplet-based method for transgene-free lineage tracing, and apply it to study hematopoiesis, capturing hundreds of clonal trajectories across almost 100,000 single-cells. Using ground-truth genetic barcodes, we demonstrate that EPI-clone accurately identifies clonal lineages throughout hematopoietic differentiation. Applied to unperturbed hematopoiesis, we describe an overall decline of clonal complexity during murine ageing and the expansion of rare low-output stem cell clones. In aged human donors, we identified expanded hematopoietic clones with and without genetic lesions, and various degrees of clonal complexity. Taken together, EPI-clone enables accurate and transgene-free single-cell lineage tracing at scale.
    DOI:  https://doi.org/10.1101/2024.04.01.587514
  24. Leukemia. 2024 Apr 13.
    Combination therapies with ponatinib and asciminib in a preclinical model of chronic myeloid leukemia blast crisis with compound mutations.
    Nikola Curik, Adam Laznicka, Vaclava Polivkova, Jitka Krizkova, Eva Pokorna, Pavel Semerak, Pavla Suchankova, Pavel Burda, Andreas Hochhaus, Katerina Machova Polakova.
      
    DOI:  https://doi.org/10.1038/s41375-024-02248-0
  25. J Clin Oncol. 2024 Apr 18. JCO2302547
    Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma.
    Chengcheng Yan, Melissa A Richard, Christopher J Gibson, Jianbo He, Alysia Bosworth, David K Crossman, Purnima Singh, Lindsey Hageman, Rashi Kalra, Saro H Armenian, Julie Vose, Daniel J Weisdorf, Benjamin L Ebert, Yutaka Yasui, Stephen J Forman, Ravi Bhatia, Smita Bhatia.
      PURPOSE: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available.METHODS: We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients.
    RESULTS: CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of DNMT3A (n = 25), PPM1D (n = 7), TET2 (n = 7), and TP53 (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSC product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without co-occurring TP53 or PPM1D mutations) did. Presence of TP53 and/or PPM1D mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality.
    CONCLUSION: The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.
    DOI:  https://doi.org/10.1200/JCO.23.02547
  26. ACS Med Chem Lett. 2024 Apr 11. 15(4): 524-532
    Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055.
    Mayako Michino, Tanweer A Khan, Michael W Miller, Yoshiyuki Fukase, Jeremie Vendome, Carolina Adura, J Fraser Glickman, Yiman Liu, Liling Wan, C David Allis, Andrew W Stamford, Peter T Meinke, Louis M Renzetti, Stacia Kargman, Nigel J Liverton, David J Huggins.
      Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and is appropriate for in vivo evaluation of the ENL YEATS inhibition mechanism in AML.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00016
  27. Prostate. 2024 Apr 20.
    Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer.
    Catherine H Marshall, Lukasz P Gondek, Violet Daniels, Changxue Lu, Sergiu Pasca, Jiajun Xie, Mark C Markowski, Channing J Paller, Laura A Sena, Samuel R Denmeade, Jun Luo, Emmanuel S Antonarakis.
      BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors are approved for the treatment of some men with advanced prostate cancer. Rare but serious side effects include myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The impact of PARP inhibitors on clonal hematopoiesis (CH), a potential precursor lesion associated with MDS and AML, is incompletely understood in prostate cancer. We hypothesized that PARP inhibitors would increase CH prevalence and abundance.METHODS: We prospectively enrolled participants with advanced prostate cancer treated with PARP inhibitors. The presence of CH was assessed from leukocytes using an ultra-deep error-corrected dual unique molecular identifiers sequencing method targeting 49 genes most commonly mutated in CH and myeloid malignancies. Variant allele frequencies (VAF) of ≥0.5% were considered clinically significant. Blood samples were collected before and after PARP inhibitor treatment.
    RESULTS: Ten men were enrolled; mean age of 67 years. Six patients had Gleason 7 disease, and four had Gleason ≥8 disease at diagnosis. Nine had localized disease at diagnosis, and eight had prior treatment with radiation. The mean time between pre- and post-treatment blood samples was 11 months (range 2.6-31 months). Six patients (60%) had CH identified prior to PARP inhibitor treatment, three with multiple clones. Of 11 CH clones identified in follow-up, 5 (45%) appeared or increased after treatment. DNMT3A, TET2, and PPM1D were the most common CH alterations observed. The largest post-treatment increase involved the PPM1D gene.
    CONCLUSION: CH alterations are frequently found after treatment with PARP inhibitors in patients with prostate cancer and this may be one mechanism by which PARP inhibitors lead to increased risk of MDS/AML.
    Keywords:  PARP inhibitors; clonal hematopoiesis; prostate cancer
    DOI:  https://doi.org/10.1002/pros.24712
  28. Crit Rev Oncol Hematol. 2024 Apr 12. pii: S1040-8428(24)00101-X. [Epub ahead of print] 104358
    A practical algorithm for acute myeloid leukaemia diagnosis following the updated 2022 classifications.
    Matteo Giovanni Della Porta, Giovanni Martinelli, Alessandro Rambaldi, Alessandra Santoro, Maria Teresa Voso.
      Disease classification of complex and heterogenous diseases, such as acute myeloid leukaemia (AML), is continuously updated to define diagnoses, appropriate treatments, and assist research and education. Recent availability of molecular profiling techniques further benefits the classification of AML. The World Health Organization (WHO) classification of haematolymphoid tumours and the International Consensus Classification of myeloid neoplasms and acute leukaemia from 2022 are two updated versions of the WHO 2016 classification. As a consequence, the European LeukemiaNet 2022 recommendations on the diagnosis and management of AML in adults have been also updated. The current review provides a practical interpretation of these guidelines to facilitate the diagnosis of AML and discusses genetic testing, disease genetic heterogeneity, and FLT3 mutations. We propose a practical algorithm for the speedy diagnosis of AML. Future classifications may need to incorporate gene mutation combinations to enable personalised treatment regimens in the management of patients with AML.
    Keywords:  AML classification; AML diagnostic workup; AML risk stratification
    DOI:  https://doi.org/10.1016/j.critrevonc.2024.104358
  29. Cell Death Dis. 2024 Apr 18. 15(4): 278
    Caspase 8 deletion causes infection/inflammation-induced bone marrow failure and MDS-like disease in mice.
    Shanhui Liu, Kanak Joshi, Lei Zhang, Wenyan Li, Ryan Mack, Austin Runde, Patrick A Hagen, Kevin Barton, Peter Breslin, Hong-Long Ji, Ameet R Kini, Zhiping Wang, Jiwang Zhang.
      Myelodysplastic syndromes (MDS) are a heterogeneous group of pre-leukemic hematopoietic disorders characterized by cytopenia in peripheral blood due to ineffective hematopoiesis and normo- or hypercellularity and morphologic dysplasia in bone marrow (BM). An inflammatory BM microenvironment and programmed cell death of hematopoietic stem/progenitor cells (HSPCs) are thought to be the major causes of ineffective hematopoiesis in MDS. Pyroptosis, apoptosis and necroptosis (collectively, PANoptosis) are observed in BM tissues of MDS patients, suggesting an important role of PANoptosis in MDS pathogenesis. Caspase 8 (Casp8) is a master regulator of PANoptosis, which is downregulated in HSPCs from most MDS patients and abnormally spliced in HSPCs from MDS patients with SRSF2 mutation. To study the role of PANoptosis in hematopoiesis, we generated inducible Casp8 knockout mice (Casp8-/-). Mx1-Cre-Casp8-/- mice died of BM failure within 10 days of polyI:C injections due to depletion of HSPCs. Rosa-ERT2Cre-Casp8-/- mice are healthy without significant changes in BM hematopoiesis within the first 1.5 months after Casp8 deletion. Such mice developed BM failure upon infection or low dose polyI:C/LPS injections due to the hypersensitivity of Casp8-/- HSPCs to infection or inflammation-induced necroptosis which can be prevented by Ripk3 deletion. However, impaired self-renewal capacity of Casp8-/- HSPCs cannot be rescued by Ripk3 deletion due to activation of Ripk1-Tbk1 signaling. Most importantly, mice transplanted with Casp8-/- BM cells developed MDS-like disease within 4 months of transplantation as demonstrated by anemia, thrombocytopenia and myelodysplasia. Our study suggests an essential role for a balance in Casp8, Ripk3-Mlkl and Ripk1-Tbk1 activities in the regulation of survival and self-renewal of HSPCs, the disruption of which induces inflammation and BM failure, resulting in MDS-like disease.
    DOI:  https://doi.org/10.1038/s41419-024-06660-3
  30. Haematologica. 2024 Apr 18.
    Validation of mutated CEBPA bZIP as a distinct prognosis entity in acute myeloid leukemia: a study by the Spanish PETHEMA registry.
    Esther Prados De la Torre, Josefina Serrano, David Martínez-Cuadrón, Laura Torres, Claudia Sargas, Rosa Ayala, Cristina Bilbao-Sieyro, María Carmen Chillón, María José Larráyoz, Elena Soria, Clara Aparicio-Pérez, Juan M Bergua, Teresa Bernal, Cristina Gil, Mar Tormo, Lorenzo Algarra, Juan M Alonso-Domínguez, Eduardo Rodriguez-Arbolí, Pilar Martínez-Sanchez, Ana Oliva, Ana M Colorado-Araujo, Carlos Rodríguez-Medina, Susana Vives, Lourdes Hermosín, Joaquín Martínez-López, Ramón García-Sanz, José A Pérez-Simón, María José Calasanz, María Teresa Gómez-Casares, Eva Barragán, Joaquín Sánchez-García J, Pau Montesinos.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.284601
  31. Leukemia. 2024 Apr 18.
    Measurable residual disease (MRD)-testing in haematological and solid cancers.
    Junren Chen, Robert Peter Gale, Yu Hu, Wen Yan, Tiantian Wang, Wei Zhang.
      
    DOI:  https://doi.org/10.1038/s41375-024-02252-4
  32. J Clin Invest. 2024 Apr 15. pii: e168536. [Epub ahead of print]134(8):
    Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.
    Tobias Suske, Helena Sorger, Gabriele Manhart, Frank Ruge, Nicole Prutsch, Mark W Zimmerman, Thomas Eder, Diaaeldin I Abdallah, Barbara Maurer, Christina Wagner, Susann Schönefeldt, Katrin Spirk, Alexander Pichler, Tea Pemovska, Carmen Schweicker, Daniel Pölöske, Emina Hubanic, Dennis Jungherz, Tony Andreas Müller, Myint Myat Khine Aung, Anna Orlova, Ha Thi Thanh Pham, Kerstin Zimmel, Thomas Krausgruber, Christoph Bock, Mathias Müller, Maik Dahlhoff, Auke Boersma, Thomas Rülicke, Roman Fleck, Elvin Dominic de Araujo, Patrick Thomas Gunning, Tero Aittokallio, Satu Mustjoki, Takaomi Sanda, Sylvia Hartmann, Florian Grebien, Gregor Hoermann, Torsten Haferlach, Philipp Bernhard Staber, Heidi Anne Neubauer, Alfred Thomas Look, Marco Herling, Richard Moriggl.
      T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
    Keywords:  Genetics; Hematology; Leukemias; T cell development; T cell receptor
    DOI:  https://doi.org/10.1172/JCI168536
  33. Ann Hematol. 2024 Apr 18.
    Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.
    Akriti G Jain, Quinto Gesiotto, Somedeb Ball, Lisa Nodzon, Amanda Rodriguez, Onyee Chan, Eric Padron, Andrew Kuykendall, Rami Komrokji, David A Sallman, Jeffrey E Lancet, Javier Pinilla-Ibarz, Kendra Sweet.
      Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.
    Keywords:  Adverse events; CML; Chronic myeloid leukemia; Dasatinib; TKI; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1007/s00277-024-05760-6
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