bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022–09–04
43 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML.
  2. Contemporary outcomes in IDH-mutated AML: The impact of co-occurring NPM1 mutations and venetoclax-based treatment.
  3. Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia.
  4. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.
  5. Cellular hierarchies predict drug response in acute myeloid leukemia.
  6. Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.
  7. Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.
  8. Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.
  9. Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML.
  10. Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function.
  11. Impact of Cytogenetic Risk on Outcomes of Non-T Cell Depleted Haploidentical Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia.
  12. Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease.
  13. Low-dose dasatinib 50 mg/day versus standard-dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: A propensity score analysis.
  14. Progenitor hierarchy of chronic myelomonocytic leukemia identifies inflammatory monocytic-biased trajectory linked to worse outcomes.
  15. RNAi screen identifies MTA1 as an epigenetic modifier of differentiation commitment in human HSPCs.
  16. Epo-IGF1R crosstalk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm.
  17. Chasing leukemia differentiation through induction therapy, relapse and transplantation.
  18. Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.
  19. Clinical outcomes and impact of therapeutic intervention in patients with acute myeloid leukemia who experience MRD recurrence following MRD-negative remission.
  20. Co-expression of mutated Jak2 and Calr enhances myeloproliferative phenotype in mice without loss of stem cell fitness.
  21. Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients.
  22. Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.
  23. EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors.
  24. Clonal Hematopoiesis and Epigenetic Age Acceleration in Elderly Danish Twins.
  25. Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia.
  26. Ferroptosis-related gene signature predicts the clinical outcome in pediatric acute myeloid leukemia patients and refines the 2017 ELN classification system.
  27. IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia.
  28. Long-term proliferation of immature hypoxia-dependent JMML cells supported by a 3D in vitro system.
  29. A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.
  30. Optical genome mapping refines cytogenetic diagnostics, prognostic stratification and provides new molecular insights in adult MDS/AML patients.
  31. Concurrent Zrsr2 mutation and Tet2 loss promote myelodysplastic neoplasm in mice.
  32. Significance of measurable residual disease in adults with secondary acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.
  33. Low-risk polycythemia vera treated with phlebotomies: clinical characteristics, hematologic control and complications in 453 patients from the Spanish Registry of Polycythemia Vera.
  34. Retrospective comparison of survival and responses to Fludarabine, Cytarabine, GCSF (FLAG) in combination with gemtuzumab ozogamicin (GO) or Idarubicin (IDA) in patients with newly diagnosed core binding factor (CBF) acute myelogenous leukemia: MD Anderson experience in 174 patients.
  35. Acquired somatic variants confirm the independent development of AML in monozygotic twins with germline CEBPA variant.
  36. Chronic Conditions, Late Mortality and Health Status After Childhood AML: A Childhood Cancer Survivor Study Report.
  37. Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.
  38. Postremission cytopenia management in patients with AML treated with venetoclax and azacitidine in VIALE-A.
  39. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
  40. The 17-gene stemness score associates with relapse risk and long-term outcomes following allogeneic haematopoietic cell transplantation in acute myeloid leukaemia.
  41. The genomic landscape of pediatric acute lymphoblastic leukemia.
  42. Clonal hematopoiesis of indeterminate potential in patients with solid tumor malignancies.
  43. A ferroptosis-related gene signature and immune infiltration patterns predict the overall survival in acute myeloid leukemia patients.
  1. Blood Adv. 2022 Aug 29. pii: bloodadvances.2022007563. [Epub ahead of print]
    Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML.
    Giulia Pianigiani, Andrea Gagliardi, Federica Mezzasoma, Francesca Rocchio, Valentina Tini, Barbara Bigerna, Paolo Sportoletti, Simona Caruso, Andrea Marra, Sara Peruzzi, Eleonora Petito, Giulio Spinozzi, Sharon Shacham, Yosef Landesman, Concetta Quintarelli, Paolo Gresele, Franco Locatelli, Maria Paola Martelli, Brunangelo Falini, Lorenzo Brunetti.
      NPM1 is the most frequently mutated gene in adult acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and XPO1 causes the aberrant cytoplasmic dislocation of NPM1c and promotes high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in NPM1-mutated patients. Here, we show that this dosing strategy results in only temporary disruption of the XPO1-NPM1c interaction, limiting the efficacy of selinexor. Since the second-generation XPO1 inhibitor eltanexor can be administered more frequently, we tested the anti-leukemic activity of prolonged XPO1 inhibition in NPM1-mutated AML models. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation and prolonged survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007563
  2. Am J Hematol. 2022 Aug 22.
    Contemporary outcomes in IDH-mutated AML: The impact of co-occurring NPM1 mutations and venetoclax-based treatment.
    Curtis A Lachowiez, Patrick K Reville, Hagop Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Daver, Ghayas Issa, Ken Furudate, Tomoyuki Tanaka, Sherry Pierce, Guilin Tang, Keyur P Patel, Jeffrey Medeiros, Hussein Abbas, Fadi Haddad, Daniel Hammond, Nicholas J Short, Abhishek Maiti, Musa Yilmaz, Koji Sasaki, Koichi Takahashi, Naveen Pemmaraju, Marina Konopleva, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia, Sanam Loghavi, Courtney D DiNardo.
      Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics; response and survival; and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1mut AML (N=119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2mut (N=229) or IDHwt /NPM1mut AML (N=208). In multivariate analysis, patients with IDH2mut (HR 0.61 [95%CI: 0.43-0.88], p-value: 0.007) or IDHwt /NPM1mut (HR 0.65 [95% CI: 0.45-0.94], p-value: 0.024) AML had a decreased risk of death versus IDH1mut AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1mut with similar OS observed between IDH1mut /NPM1wt , IDH2mut /NPM1wt , and IDHwt /NPM1mut AML. With regards to the influence of IDHmut /NPM1mut cases, IC improved survival in IDH2mut /NPM1mut vs. IDH2mut /NPM1wt AML (HR: 0.54 [95% CI: 0.2644-1.082], p-value: 0.077), while venetoclax-based therapy improved survival in IDH1mut /NPM1mut vs. IDH1mut /NPM1mut AML (HR: 0.094 [95% CI: 0.01-0.74], p-value: 0.0056). Differing outcomes were observed in IDH1mut vs. IDH2mut or NPM1mut AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26694
  3. Cancer Discov. 2022 Sep 02. pii: CD-21-1307. [Epub ahead of print]
    Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia.
    Yiman Liu, Qinglan Li, Fatemeh Alikarami, Declan R Barrett, Leila Mahdavi, Hangpeng Li, Sylvia Tang, Tanweer A Khan, Mayako Michino, Connor Hill, Lele Song, Lu Yang, Yuanyuan Li, Sheela Pangeni Pokharel, Andrew W Stamford, Nigel Liverton, Louis M Renzetti, Simon Taylor, Gillian F Watt, Tammy Ladduwahetty, Stacia Kargman, Peter T Meinke, Michael A Foley, Junwei Shi, Haitao Li, Martin Carroll, Chun-Wei Chen, Alessandro Gardini, Ivan Maillard, David J Huggins, Kathrin M Bernt, Liling Wan.
      The chromatin reader eleven-nineteen-leukemia (ENL) has been identified as a critical dependency in AML, but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support clinical translation of this approach.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1307
  4. Am J Hematol. 2022 Aug 12.
    Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.
    Hagop M Kantarjian, Elias Jabbour, Michael Deininger, Elisabetta Abruzzese, Jane Apperley, Jorge Cortes, Charles Chuah, Daniel J DeAngelo, John DiPersio, Andreas Hochhaus, Jeffrey Lipton, Franck E Nicolini, Javier Pinilla-Ibarz, Delphine Rea, Gianantonio Rosti, Philippe Rousselot, Neil P Shah, Moshe Talpaz, Shouryadeep Srivastava, Xiaowei Ren, Michael Mauro.
      Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.
    DOI:  https://doi.org/10.1002/ajh.26686
  5. Cancer Cell. 2022 Aug 26. pii: S1535-6108(22)00383-X. [Epub ahead of print]
    Cellular hierarchies predict drug response in acute myeloid leukemia.
    Simon Raffel, Lars Velten, Simon Haas.
      In a recent Nature Medicine study, Zeng and colleagues integrate both genomic and stem cell models of acute myeloid leukemia (AML) by deconvoluting cellular hierarchies of more than 1,000 AML samples. This work introduces a framework capable of predicting drug responses to targeted therapies in future clinical trials.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.019
  6. Elife. 2022 Sep 02. pii: e75908. [Epub ahead of print]11
    Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.
    Nuria Vilaplana-Lopera, Vincent Cuminetti, Ruba Almaghrabi, Grigorios Papatzikas, Ashok Kumar Rout, Mark Jeeves, Elena González, Yara Alyahyawi, Alan Cunnigham, Ayşegüll Erdem, Frank Schnütgen, Manoj Raghavan, Sandeep Potluri, Jean-Baptiste Cazier, Jan Jacob Schuringa, Michelle A C Reed, Lorena Arranz, Ulrich Günther, Paloma Garcia.
      Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy.
    Keywords:  biochemistry; cancer biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.75908
  7. Blood Adv. 2022 Aug 31. pii: bloodadvances.2022007486. [Epub ahead of print]
    Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.
    Mohammad Azhar, Zachary Kincaid, Meenu Kesarwani, Jacob Menke, Joshua Sweiterman, Sekhu Ansari, Angela Reaves, Arhama Ahmed, Rammsha Shahzad, Areeba Khan, Nuha Syed, Noor Amir, Mark Wunderlich, Tahir Latif, William L Seibel, Mohammad Azam.
      Despite significant advancement in developing selective FLT3 inhibitors, resistance to treatment is common even on continued therapy. Acquisition of on-target mutations or adaptation to MAPK, JAK2, and ABL signaling pathways drive treatment failure and disease relapse. While combinatorial targeting of all escape routes in pre-clinical models demonstrated its efficacy, its clinical application is challenging due to drug-drug interaction and differing pharmacokinetics of the inhibitors. We reasoned that selective polypharmacology targeting could lead to a durable response with reduced toxicity. A cell-based screening was carried out to identify inhibitors targeting FLT3, RAS-MAPK, BCR-ABL, and JAK2 to target the adaptive resistance observed with FLT3 inhibitors. Here we show that pluripotin is an equipotent inhibitor of FLT3, BCR-ABL, and JAK2, in addition to inhibiting Ras-GAP and ERK1. Structural modeling studies revealed that pluripotin is a type-II kinase inhibitor that selectively binds with inactive conformations of FLT3, ABL, and JAK2. Pluripotin showed potent inhibitory activity on both mouse and human cells expressing FLT3ITD, including clinically challenging resistant mutations of the gatekeeper residue, F691L. Likewise, pluripotin suppressed the adaptive resistance conferred by the activation of RAS-MAPK pathways, BCR-ABL, and JAK2 signaling. Pluripotin treatment curbed the progression of AML in multiple in vivo models including patient-derived primary AML cells in mouse xenotransplants. As a proof of concept, we demonstrate that targeted polypharmacological inhibition of key signaling nodes driving adaptive resistance can provide a durable response.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007486
  8. Elife. 2022 Aug 30. pii: e78136. [Epub ahead of print]11
    Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.
    Gaurav S Choudhary, Andrea Pellagatti, Bogos Agianian, Molly A Smith, Tushar D Bhagat, Shanisha Gordon-Mitchell, Srabani Sahu, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Ritesh Aggarwal, Sarah Aminov, Leya Schwartz, Violetta Steeples, Robert N Booher, Murali Ramachandra, Maria Samson, Milagros Carbajal, Kith Pradhan, Teresa V Bowman, Manoj M Pillai, Britta Will, Amittha Wickrema, Aditi Shastri, Robert K Bradley, Robert E Martell, Ulrich G Steidl, Evripidis Gavathiotis, Jacqueline Boultwood, Daniel T Starczynowski, Amit Verma.
       Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood.
    Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML.
    Results: RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models.
    Conclusions: SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.
    Funding: This work was supported by Cincinnati Children's Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle's Angel Foundation for Cancer Research, and Edward P. Evans Foundation grants to DTS. AV is supported by Edward P. Evans Foundation, National Institute of Health (R01HL150832, R01HL139487, R01CA275007), Leukemia and Lymphoma Society, Curis and a gift from the Jane and Myles P. Dempsey family. AP and JB are supported by Blood Cancer UK (grants 13042 and 19004). GC is supported by a training grant from NYSTEM. We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420).
    Keywords:  AML; CA4948; Emavusertib; IRAK4; MDS; SF3B1; human; medicine
    DOI:  https://doi.org/10.7554/eLife.78136
  9. Leukemia. 2022 Sep 02.
    Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML.
    Catana Allert, Alexander Waclawiczek, Sarah Miriam Naomi Zimmermann, Stefanie Göllner, Daniel Heid, Maike Janssen, Simon Renders, Christian Rohde, Marcus Bauer, Margarita Bruckmann, Rafael Zinz, Cornelius Pauli, Birgit Besenbeck, Claudia Wickenhauser, Andreas Trumpp, Jeroen Krijgsveld, Carsten Müller-Tidow, Maximilian Felix Blank.
      FLT3 tyrosine kinase inhibitor (TKI) therapy evolved into a standard therapy in FLT3-mutated AML. TKI resistance, however, develops frequently with poor outcomes. We analyzed acquired TKI resistance in AML cell lines by multilayered proteome analyses. Leupaxin (LPXN), a regulator of cell migration and adhesion, was induced during early resistance development, alongside the tyrosine kinase PTK2B which phosphorylated LPXN. Resistant cells differed in cell adhesion and migration, indicating altered niche interactions. PTK2B and LPXN were highly expressed in leukemic stem cells in FLT3-ITD patients. PTK2B/FAK inhibition abrogated resistance-associated phenotypes, such as enhanced cell migration. Altered pathways in resistant cells, assessed by nascent proteomics, were largely reverted upon PTK2B/FAK inhibition. PTK2B/FAK inhibitors PF-431396 and defactinib synergized with different TKIs or daunorubicin in FLT3-mutated AML. Midostaurin-resistant and AML cells co-cultured with mesenchymal stroma cells responded particularly well to PTK2B/FAK inhibitor addition. Xenograft mouse models showed significant longer time to leukemia symptom-related endpoint upon gilteritinib/defactinib combination treatment in comparison to treatment with either drug alone. Our data suggest that the leupaxin-PTK2B axis plays an important role in acquired TKI resistance in AML. PTK2B/FAK inhibitors act synergistically with currently used therapeutics and may overcome emerging TKI resistance in FLT3-mutated AML at an early timepoint.
    DOI:  https://doi.org/10.1038/s41375-022-01687-x
  10. Blood Adv. 2022 Aug 31. pii: bloodadvances.2022008242. [Epub ahead of print]
    Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function.
    Yoshikane Kikushige, Toshihiro Miyamoto, Yu Kochi, Yuichiro Semba, Maki Ohishi, Hidetoshi Irifune, Kiwamu Hatakeyama, Yuya Kunisaki, Takeshi Sugio, Teppei Sakoda, Kohta Miyawaki, Koji Kato, Tomoyoshi Soga, Koichi Akashi.
      Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia-specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), and primary human acute myelogenous leukemia (AML) and lymphoblastic leukemia (ALL) cells. Here we show that human leukemia addicts to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG) and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids (BCKAs), whose metabolic processes provide leukemia cells with critical substrates for the TCA cycle and the non-essential amino acids synthesis, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates polycomb repressive complex 2 (PRC2) function, an epigenetic regulator for stem cell signatures, through inhibiting transcription of PRC components, such as zeste homolog 2 (EZH2) and embryonic ectoderm development (EED). Accordingly, BCAA catabolism plays an important role in maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008242
  11. Transplant Cell Ther. 2022 Aug 25. pii: S2666-6367(22)01556-1. [Epub ahead of print]
    Impact of Cytogenetic Risk on Outcomes of Non-T Cell Depleted Haploidentical Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia.
    Arnon Nagler, Myriam Labopin, Bhagirathbhai Dholaria, Fabio Ciceri, Alessia Fraccaroli, Didier Blaise, Renato Fanin, Benedetto Bruno, Edouard Forcade, Jan Vydra, Patrice Chevallier, Claude Eric Bulabois, Pavel Jindra, Martin Bornhäuser, Jonathan Canaani, Jaime Sanz, Bipin N Savani, Alexandros Spyridonidis, Sebastian Giebel, Eolia Brissot, Ali Bazarbachi, Jordi Esteve, Mohamad Mohty.
       BACKGROUND: Baseline cytogenetics and disease status are key factors predicting the outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML). The importance of cytogenetic risk in patients with primary refractory or relapsed (R/R) AML undergoing haploidentical (Haplo) HCT is unknown. We studied the impact of cytogenetic risk in patients with R/R de novo AML with active disease who underwent non-T cell depleted Haplo-HCT with post-transplant cyclophosphamide from 2010-2020.
    OBJECTIVES: Four hundred and forty patients with active disease at transplantation from EBMT database were analyzed [291 (66.1%) with intermediate-risk (AMLint) and 149 (44.1%) with adverse-risk cytogenetics (AMLadv)]. Impact of baseline cytogenetic risk on various transplant outcomes was evaluated.
    RESULTS: Pre-transplant disease status was relapse in 48.1% and 26.8% and primary refractory in 51.9% and 73.2% of the patients with AMLint and AMLadv, respectively (p<0.0001). Two-year leukemia-free survival (LFS, 35.5% vs. 15.5%, p=0.001) and overall survival (OS, 39.2% vs. 20.1%, p=0.001) were better in AMLint versus AMLadv. In multivariate analysis, the relapse rate was significantly higher [hazard ratio (HR)=2.17 (95% CI 1.57-3.0)] and LFS [HR=1.71 (95% CI 1.31-2.22)] and OS [HR=1.69 (95% CI 1.29-2.22)], significantly lower for patients with AMLadv compared to AMLint, conditioning intensity did not affect leukemia relapse rate. Non-relapse mortality [HR=1.1 (95% CI: 0.7-1.74)] and GVHD-free, relapse-free survival [GRFS, HR=1.37 (95% CI: 1.06-1.77)] did not differ significantly between the risk groups. Disease status before transplant (primary refractory versus relapsed) or conditioning intensity did not impact main transplant outcomes.
    CONCLUSION: Baseline cytogenetic risk remains a key prognostic factor for patients with R/R AML with persistent disease before non-T cell depleted Haplo-HCT.
    Keywords:  Allogeneic stem cell transplantation; acute myeloid leukemia; cytogenetic risk; haploidentical; post-transplant cyclophosphamide; relapse
    DOI:  https://doi.org/10.1016/j.jtct.2022.08.018
  12. J Hematol Oncol. 2022 Aug 31. 15(1): 124
    Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease.
    Razan Mohty, Rama Al Hamed, Ali Bazarbachi, Eolia Brissot, Arnon Nagler, Amer Zeidan, Mohamad Mohty.
      Myelodysplastic syndromes (MDS) are a heterogeneous clonal disease of myeloid neoplasms characterized by ineffective hematopoiesis, variable degree of cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Molecular and genetic characterization of MDS has led to a better understanding of the disease pathophysiology and is leading to the development of novel therapies. Targeted and immune therapies have shown promising results in different hematologic malignancies. However, their potential use in MDS is yet to be fully defined. Here, we review the most recent advances in therapeutic approaches in MDS, focusing on higher-risk disease. Allogeneic hematopoietic cell transplantation is beyond the scope of this article.
    Keywords:  High-risk MDS; Immune dysregulation; Immunotherapy; Myeloid malignancy; Precision medicine; Targeted therapy
    DOI:  https://doi.org/10.1186/s13045-022-01346-9
  13. Am J Hematol. 2022 Aug 13.
    Low-dose dasatinib 50 mg/day versus standard-dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: A propensity score analysis.
    Elias Jabbour, Koji Sasaki, Fadi G Haddad, Ghayas C Issa, Jeffrey Skinner, Sara Dellasala, Musa Yilmaz, Alessandra Ferrajoli, Prithviraj Bose, Philip Thompson, Yesid Alvarado, Nitin Jain, Guillermo Garcia-Manero, Koichi Takahashi, Gautam Borthakur, Naveen Pemmaraju, Sherry Pierce, Hagop Kantarjian.
      Low-dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). No randomized trials have compared the outcome with standard-dose dasatinib. This study aims to compare the outcome of patients with CML-CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML-CP treated with low-dose dasatinib (N = 83) or standard-dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4, and MR4.5. Failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) were also compared. Patients on low-dose dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow-up time was 60 months. The 3-year MMR rates were 92% and 84% for low-dose and standard-dose dasatinib, respectively (p = .23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% vs. 66%; p = .04) and MR4.5 (77% vs. 62%; p = .02) at 3 years. The 4-year FFS, EFS and OS rates were 89% versus 77% (p = .04), 95% versus 92% (p = .06), and 97% versus 96% (p = .78) with low-dose and standard-dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure.
    DOI:  https://doi.org/10.1002/ajh.26689
  14. Blood Cancer Discov. 2022 Sep 02. pii: BCD-21-0217. [Epub ahead of print]
    Progenitor hierarchy of chronic myelomonocytic leukemia identifies inflammatory monocytic-biased trajectory linked to worse outcomes.
    Meghan C Ferrall-Fairbanks, Abhishek Dhawan, Brian Johnson, Hannah Newman, Virginia Volpe, Christopher Letson, Markus Ball, Anthony M Hunter, Maria E Balasis, Traci Kruer, Nana Adjoa Ben-Crentsil, Jodi L Kroeger, Robert Balderas, Rami S Komrokji, David A Sallman, Jing Zhang, Rafael Bejar, Philipp M Altrock, Eric Padron.
      Myeloblast expansion is a hallmark of disease progression and comprises CD34+ hematopoietic stem and progenitor cells (HSPC). How this compartment evolves during disease progression in chronic myeloid neoplasms is unknown. Using scRNA-sequencing and high-parameter flow cytometry, we show that CMML CD34+ HSPCs can be classified into three differentiation trajectories: monocytic, megakaryocyte-erythroid progenitor (MEP), and normal-like. Hallmarks of monocytic-biased trajectory were enrichment of CD120b+ inflammatory granulocyte-macrophage progenitor (GMP)-like cells, activated cytokine receptor signaling, phenotypic HSC depletion and adverse outcomes. Cytokine receptor diversity was generally an adverse feature and elevated in CD120b+ GMPs. Hypomethylating agents decreased monocytic-biased cells in CMML patients. Given the enrichment of RAS pathway mutations in monocytic-biased cells, NRAS competitive transplants and LPS-treated xenograft models recapitulated monocytic-biased CMML, suggesting that hematopoietic stress precipitates the monocytic-biased state. Deconvolution of HSPC compartments in other myeloid neoplasms and identifying therapeutic strategies to mitigate the monocytic-biased differentiation trajectory should be explored.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0217
  15. Exp Hematol. 2022 Aug 27. pii: S0301-472X(22)00680-4. [Epub ahead of print]
    RNAi screen identifies MTA1 as an epigenetic modifier of differentiation commitment in human HSPCs.
    Kristijonas Žemaitis, Agatheeswaran Subramaniam, Roman Galeev, Aurel Prosz, Maria Jassinskaja, Jenny Hansson, Jonas Larsson.
      The molecular mechanisms regulating key fate decisions of hematopoietic stem cells (HSCs) remain incompletely understood. Here, we targeted global shRNA libraries to primary human hematopoietic stem and progenitor cells (HSPCs) to screen for modifiers of self-renewal and differentiation, and identified metastasis-associated 1 (MTA1) as a negative regulator of human HSPC propagation in vitro. Knockdown of MTA1 by independent shRNAs in primary human cord blood (CB) HSPCs led to a cell expansion during culture and a relative accumulation of immature CD34+CD90+ cells with perturbed in vitro differentiation potential. Transplantation experiments in immunodeficient mice showed a significant reduction of human chimerism in both blood and bone marrow from HSPCs with knockdown of MTA1, possibly due to reduced maturation of blood cells. We further show that MTA1 associates with the nucleosome remodeling deacetylase (NuRD) complex in human HSPCs, and upon knockdown of MTA1 we observed an increase in H3K27Ac marks coupled with a downregulation of genes linked to differentiation towards the erythroid lineage. Altogether, our findings identify MTA1 as a novel regulator of human HSPCs in vitro and in vivo with critical functions for differentiation commitment.
    Keywords:  Epigenetic regulation; Hematopoiesis; MTA1; Stem cell expansion; shRNA screen
    DOI:  https://doi.org/10.1016/j.exphem.2022.08.004
  16. Blood. 2022 Sep 02. pii: blood.2022016741. [Epub ahead of print]
    Epo-IGF1R crosstalk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm.
    Hsi-Hsien Hsieh, Huiyu Yao, Yue Ma, Yuannyu Zhang, Xue Xiao, Helen Stephens, Naureen Wajahat, Stephen S Chung, Lin Xu, Jian Xu, Raajit K Rampal, Lily Jun-Shen Huang.
      We find that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with CFU-E activity (stress CFU-E/sCFU-E) is markedly expanded to restore the erythron. sCFU-E are targets of erythropoietin (Epo) and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2/STAT5-dependent expression of IRS2, thus engaging the pro-growth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R/IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant, JAK2(V617F), in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In myeloproliferative neoplasm patient samples, the number of sCFU-E like cells increases, and inhibition of IGR1R/IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identify a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.
    DOI:  https://doi.org/10.1182/blood.2022016741
  17. Blood Rev. 2022 Aug 12. pii: S0268-960X(22)00074-1. [Epub ahead of print] 101000
    Chasing leukemia differentiation through induction therapy, relapse and transplantation.
    Jennifer N Saultz, Jeffrey W Tyner.
      Despite rapid advances in our understanding of acute myeloid leukemia (AML), the disease remains challenging to treat with 5-year survival for adult patients 20 years or older estimated to be 26% (Cancer 2021). The use of new targeted therapies including BCL2, IDH1/IDH2, and FLT3 inhibitors has revolutionized treatment approaches but also changed the disease trajectory with unique modes of resistance. Recent studies have shown that stem cell maturation state drives expression level and/or dependence on various pathways, critical to determining drug response. Instead of anticipating these changes, we remain behind the curve chasing the next expanded clone. This review will focus on current approaches to treatment in AML, including defining the significance of blast differentiation state on chemotherapeutic response, signaling pathway dependence, metabolism, immune response, and phenotypic changes. We conclude that multimodal treatment approaches are necessary to target both the immature and mature clones, thereby, sustaining drug response.
    Keywords:  AML; Chemotherapy; Differentiation; LSC; Maturation; Review
    DOI:  https://doi.org/10.1016/j.blre.2022.101000
  18. J Clin Oncol. 2022 Sep 02. JCO2200710
    Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.
    Carmelo Gurnari, Simona Pagliuca, Pedro Henrique Prata, Jacques-Emmanuel Galimard, Luiz Fernando B Catto, Lise Larcher, Marie Sebert, Vincent Allain, Bhumika J Patel, Arda Durmaz, Andre L Pinto, Mariana C B Inacio, Lucie Hernandez, Nathalie Dhedin, Sophie Caillat-Zucman, Emmanuelle Clappier, Flore Sicre de Fontbrune, Maria Teresa Voso, Valeria Visconte, Régis Peffault de Latour, Jean Soulier, Rodrigo T Calado, Gérard Socié, Jaroslaw P Maciejewski.
       PURPOSE: Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions.
    PATIENTS AND METHODS: We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution.
    RESULTS: Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1, SETBP1, RUNX1, and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, whereas myeloid driver lesions marked the group with a higher risk.
    CONCLUSION: The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.
    DOI:  https://doi.org/10.1200/JCO.22.00710
  19. Am J Hematol. 2022 Aug 24.
    Clinical outcomes and impact of therapeutic intervention in patients with acute myeloid leukemia who experience MRD recurrence following MRD-negative remission.
    Nicholas J Short, Walid Macaron, Tapan Kadia, Courtney Dinardo, Ghayas C Issa, Naval Daver, Sa Wang, Jeff Jorgensen, Daniel Nguyen, Aram Bidikian, Keyur P Patel, Sanam Loghavi, Marina Konopleva, Musa Yilmaz, Elias Jabbour, Abhishek Maiti, Hussein A Abbas, Elizabeth Shpall, Uday Popat, Gheath Al-Atrash, Sherry Pierce, Hagop M Kantarjian, Farhad Ravandi.
      
    DOI:  https://doi.org/10.1002/ajh.26698
  20. Am J Hematol. 2022 Aug 11.
    Co-expression of mutated Jak2 and Calr enhances myeloproliferative phenotype in mice without loss of stem cell fitness.
    Christina M Schueller, Andrea Majoros, Harini Nivarthi, Robert Kralovics.
      
    DOI:  https://doi.org/10.1002/ajh.26688
  21. Leukemia. 2022 Aug 30.
    Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients.
    Barbara Mora, Paola Guglielmelli, Andrew Kuykendall, Elisa Rumi, Margherita Maffioli, Francesca Palandri, Valerio De Stefano, Marianna Caramella, Silvia Salmoiraghi, Jean-Jacques Kiladjian, Jason Gotlib, Alessandra Iurlo, Francisco Cervantes, Marco Ruggeri, Richard T Silver, Francesco Albano, Giulia Benevolo, David M Ross, Matteo G Della Porta, Timothy Devos, Giada Rotunno, Rami S Komrokji, Ilaria C Casetti, Michele Merli, Marco Brociner, Domenica Caramazza, Giuseppe Auteri, Tiziano Barbui, Daniele Cattaneo, Lorenza Bertù, Luca Arcaini, Alessandro M Vannucchi, Francesco Passamonti.
      Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.
    DOI:  https://doi.org/10.1038/s41375-022-01673-3
  22. J Exp Med. 2022 Nov 07. pii: e20212228. [Epub ahead of print]219(11):
    Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.
    Ujunwa Cynthia Okoye-Okafor, Komal K Javarappa, Dimitrios Tsallos, Joseph Saad, Daozheng Yang, Chi Zhang, Lumie Benard, Victor J Thiruthuvanathan, Sally Cole, Stephen Ruiz, Madhuri Tatiparthy, Gaurav Choudhary, Stefanie DeFronzo, Boris A Bartholdy, Celine Pallaud, Pedro Marques Ramos, Aditi Shastri, Amit Verma, Caroline A Heckman, Britta Will.
      Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant-ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.
    DOI:  https://doi.org/10.1084/jem.20212228
  23. J Exp Med. 2022 Nov 07. pii: e20212437. [Epub ahead of print]219(11):
    EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors.
    Aurelie Lenaerts, Iwo Kucinski, Ward Deboutte, Marta Derecka, Pierre Cauchy, Thomas Manke, Berthold Göttgens, Rudolf Grosschedl.
      Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.
    DOI:  https://doi.org/10.1084/jem.20212437
  24. Hemasphere. 2022 Sep;6(9): e768
    Clonal Hematopoiesis and Epigenetic Age Acceleration in Elderly Danish Twins.
    Mette Soerensen, Morten Tulstrup, Jakob Werner Hansen, Joachim Weischenfeldt, Kirsten Grønbæk, Kaare Christensen.
      Clonal hematopoiesis of indeterminate potential (CHIP) is common in the elderly and has been reported to associate with accelerated epigenetic age (AgeAccel), especially intrinsic (ie, cell-type independent) AgeAccel and to a lesser degree extrinsic AgeAccel, which reflects the immune-cell composition of the peripheral blood. We investigated the association between CHIP occurrence and AgeAccel in 154 Danish twin pairs aged 73-90 years (mean 79), using both individual-level and intrapair analyses, the latter to control for shared genetic and environmental factors. Of 308 individuals, 116 carried a CHIP mutation. CHIP carriers had non-significantly increased AgeAccel compared with non-carriers; the strongest association was for the Intrinsic Epigenetic Age Acceleration (IEAA) estimator (CHIP carriers 1.4 years older, P = 0.052). In intrapair analyses, the extrinsic Hannum age estimator showed the strongest association (1.6 years older, P = 0.027). In mutation-specific analyses, TET2 mutations were associated with the extrinsic Hannum age estimator in both individual-level (3.0 years older, P = 0.003) and intrapair analyses (2.8 years older, P = 0.05). DNMT3A mutations were associated with IEAA in individual-level (1.9 years older, P = 0.034) but not intrapair analysis (0.9 years, P = 0.41). Analyses of logit-transformed variant allele frequency were generally consistent with these results. Together, these observations indicate that different factors may be driving the expansion of DNMT3A and TET2 clones, respectively. Finally, CHIP carriers accelerated in both the Hannum and the GrimAge age estimators did not have an increased mortality risk in our cohort followed for 22 years (HR = 1.02, P = 0.93), hence not replicating the stratification model proposed by Nachun et al.
    DOI:  https://doi.org/10.1097/HS9.0000000000000768
  25. Nat Commun. 2022 Aug 30. 13(1): 4501
    Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia.
    Tomoya Isobe, Masatoshi Takagi, Aiko Sato-Otsubo, Akira Nishimura, Genta Nagae, Chika Yamagishi, Moe Tamura, Yosuke Tanaka, Shuhei Asada, Reina Takeda, Akiho Tsuchiya, Xiaonan Wang, Kenichi Yoshida, Yasuhito Nannya, Hiroo Ueno, Ryo Akazawa, Itaru Kato, Takashi Mikami, Kentaro Watanabe, Masahiro Sekiguchi, Masafumi Seki, Shunsuke Kimura, Mitsuteru Hiwatari, Motohiro Kato, Shiro Fukuda, Kenji Tatsuno, Shuichi Tsutsumi, Akinori Kanai, Toshiya Inaba, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Rishi S Kotecha, Mark N Cruickshank, Fumihiko Ishikawa, Tomohiro Morio, Mariko Eguchi, Takao Deguchi, Nobutaka Kiyokawa, Yuki Arakawa, Katsuyoshi Koh, Yuki Aoki, Takashi Ishihara, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Shuki Mizutani, Nicola K Wilson, Berthold Göttgens, Satoru Miyano, Toshio Kitamura, Susumu Goyama, Akihiko Yokoyama, Hiroyuki Aburatani, Seishi Ogawa, Junko Takita.
      KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
    DOI:  https://doi.org/10.1038/s41467-022-32266-4
  26. Front Mol Biosci. 2022 ;9 954524
    Ferroptosis-related gene signature predicts the clinical outcome in pediatric acute myeloid leukemia patients and refines the 2017 ELN classification system.
    Yu Tao, Li Wei, Hua You.
      Background: The prognostic roles of ferroptosis-related mRNAs (FG) and lncRNAs (FL) in pediatric acute myeloid leukemia (P-AML) patients remain unclear. Methods: RNA-seq and clinical data of P-AML patients were downloaded from the TARGET project. Cox and LASSO regression analyses were performed to identify FG, FL, and FGL (combination of FG and FL) prognostic models, and their performances were compared. Tumor microenvironment, functional enrichment, mutation landscape, and anticancer drug sensitivity were analyzed. Results: An FGL model of 22 ferroptosis-related signatures was identified as an independent parameter, and it showed performance better than FG, FL, and four additional public prognostic models. The FGL model divided patients in the discovery cohort (N = 145), validation cohort (N = 111), combination cohort (N = 256), and intermediate-risk group (N = 103) defined by the 2017 European LeukemiaNet (ELN) classification system into two groups with distinct survival. The high-risk group was enriched in apoptosis, hypoxia, TNFA signaling via NFKB, reactive oxygen species pathway, oxidative phosphorylation, and p53 pathway and associated with low immunity, while patients in the low-risk group may benefit from anti-TIM3 antibodies. In addition, patients within the FGL high-risk group might benefit from treatment using SB505124_1194 and JAK_8517_1739. Conclusion: Our established FGL model may refine and provide a reference for clinical prognosis judgment and immunotherapies for P-AML patients.
    Keywords:  ferroptosis; immune checkpoint (ICP); immune infiltration; pediatric acute myeloid leukemia; prognostic model
    DOI:  https://doi.org/10.3389/fmolb.2022.954524
  27. J Clin Invest. 2022 Sep 01. pii: e152585. [Epub ahead of print]132(17):
    IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia.
    Jani Huuhtanen, Mette Ilander, Bhagwan Yadav, Olli Mj Dufva, Hanna Lähteenmäki, Tiina Kasanen, Jay Klievink, Ulla Olsson-Strömberg, Jesper Stentoft, Johan Richter, Perttu Koskenvesa, Martin Höglund, Stina Söderlund, Arta Dreimane, Kimmo Porkka, Tobias Gedde-Dahl, Björn T Gjertsen, Leif Stenke, Kristina Myhr-Eriksson, Berit Markevärn, Anna Lübking, Andreja Dimitrijevic, Lene Udby, Ole Weis Bjerrum, Henrik Hjorth-Hansen, Satu Mustjoki.
      In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function.
    Keywords:  Bioinformatics; Cancer immunotherapy; Hematology; Immunology; Leukemias
    DOI:  https://doi.org/10.1172/JCI152585
  28. Blood Adv. 2022 Sep 02. pii: bloodadvances.2021006746. [Epub ahead of print]
    Long-term proliferation of immature hypoxia-dependent JMML cells supported by a 3D in vitro system.
    Alice Cani, Caterina Tretti Parenzan, Chiara Frasson, Elena Rampazzo, Pamela Scarparo, Samuela Francescato, Federico Caicci, Vito Barbieri, Antonio Rosato, Simone Cesaro, Marco Zecca, Concetta Micalizzi, Laura Sainati, Martina Pigazzi, Alessandra Biffi, Barbara Buldini, Franco Locatelli, Luca Persano, Riccardo Masetti, Geertruij Te Kronnie, Silvia Bresolin.
      Juvenile myelomonocytic leukemia (JMML) is a rare, clonal stem cell disorder occurring in early childhood and characterized by RAS pathway hyperactivation in 95% of patients. JMML is characterized by a hyperproliferation of granulocytes and monocytes, and little is known about the heterogeneous nature of leukemia-initiating cells, as well as of the cellular hierarchy of the JMML bone marrow (BM). In this study, we report on the generation and characterization of a novel patient-derived three-dimensional (3D) in vitro JMML model, called pd-JAO, sustaining long-term proliferation of JMML cells with stem cell features and patient-specific hallmarks. JMML cells brewed in the 3D model under different microenvironmental conditions acquired a proliferative and survival advantage when placed at low oxygen tension. Transcriptomic and microscopic analysis revealed the activation of specific metabolic energy pathways and the inactivation of processes leading to cell death. Furthermore, we demonstrated the pd-JAO derived cells' migratory, propagation and self-renewal capacities. Our study contributes to the development of a robust JMML 3D in vitro model to study and define the impact of microenvironment stimuli on JMML disease and the molecular mechanisms regulating JMML initiating and propagating cells. Pd-JAO may become a promising model for compound tests focusing on new therapeutic intervention aiming to eradicate JMML progenitors and control JMML disease.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006746
  29. Leukemia. 2022 Aug 29.
    A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.
    Monika M Kutyna, Chung Hoow Kok, Yoon Lim, Elizabeth Ngoc Hoa Tran, David Campbell, Sharon Paton, Chloe Thompson-Peach, Kelly Lim, Dimitrios Cakouros, Agnes Arthur, Timothy Hughes, Sharad Kumar, Daniel Thomas, Stan Gronthos, Devendra K Hiwase.
      Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and β-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.
    DOI:  https://doi.org/10.1038/s41375-022-01686-y
  30. Blood Cancer J. 2022 Sep 02. 12(9): 126
    Optical genome mapping refines cytogenetic diagnostics, prognostic stratification and provides new molecular insights in adult MDS/AML patients.
    Estelle Balducci, Sophie Kaltenbach, Patrick Villarese, Eugénie Duroyon, Loria Zalmai, Chloé Friedrich, Felipe Suarez, Ambroise Marcais, Didier Bouscary, Justine Decroocq, Rudy Birsen, Michaëla Fontenay, Marie Templé, Chantal Brouzes, Aurore Touzart, Thomas Steimlé, Agata Cieslak, Ludovic Lhermitte, Carole Almire, Nicolas Chapuis, Olivier Hermine, Vahid Asnafi, Olivier Kosmider, Lucile Couronné.
      
    DOI:  https://doi.org/10.1038/s41408-022-00718-1
  31. Leukemia. 2022 Aug 27.
    Concurrent Zrsr2 mutation and Tet2 loss promote myelodysplastic neoplasm in mice.
    Cristian Garcia-Ruiz, Cristina Martínez-Valiente, Lourdes Cordón, Alessandro Liquori, Raúl Fernández-González, Eva Pericuesta, Juan Sandoval, José Cervera, Alfonso Gutiérrez-Adán, Alejandra Sanjuan-Pla.
      RNA splicing and epigenetic gene mutations are the most frequent genetic lesions found in patients with myelodysplastic neoplasm (MDS). About 25% of patients present concomitant mutations in such pathways, suggesting a cooperative role in MDS pathogenesis. Importantly, mutations in the splicing factor ZRSR2 frequently associate with alterations in the epigenetic regulator TET2. However, the impact of these concurrent mutations in hematopoiesis and MDS remains unclear. Using CRISPR/Cas9 genetically engineered mice, we demonstrate that Zrsr2m/mTet2-/- promote MDS with reduced penetrance. Animals presented peripheral blood cytopenia, splenomegaly, extramedullary hematopoiesis, and multi-lineage dysplasia, signs consistent with MDS. We identified a myelo-erythroid differentiation block accompanied by an expansion of LT-HSC and MPP2 progenitors. Transplanted animals presented a similar phenotype, thus indicating that alterations were cell-autonomous. Whole-transcriptome analysis in HSPC revealed key alterations in ribosome, inflammation, and migration/motility processes. Moreover, we found the MAPK pathway as the most affected target by mRNA aberrant splicing. Collectively, this study shows that concomitant Zrsr2 mutation and Tet2 loss are sufficient to initiate MDS in mice. Understanding this mechanistic interplay will be crucial for the identification of novel therapeutic targets in the spliceosome/epigenetic MDS subgroup.
    DOI:  https://doi.org/10.1038/s41375-022-01674-2
  32. Bone Marrow Transplant. 2022 Aug 27.
    Significance of measurable residual disease in adults with secondary acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.
    Eduardo Rodríguez-Arbolí, Corentin Orvain, Megan Othus, Roland B Walter.
      
    DOI:  https://doi.org/10.1038/s41409-022-01794-4
  33. Ann Hematol. 2022 Aug 30.
    Low-risk polycythemia vera treated with phlebotomies: clinical characteristics, hematologic control and complications in 453 patients from the Spanish Registry of Polycythemia Vera.
    On behalf of the MPN Spanish Group (GEMFIN)
      Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.
    Keywords:  Low-risk; Myelofibrosis; Phlebotomies; Polycythemia vera; Thrombosis
    DOI:  https://doi.org/10.1007/s00277-022-04963-z
  34. Am J Hematol. 2022 Aug 26.
    Retrospective comparison of survival and responses to Fludarabine, Cytarabine, GCSF (FLAG) in combination with gemtuzumab ozogamicin (GO) or Idarubicin (IDA) in patients with newly diagnosed core binding factor (CBF) acute myelogenous leukemia: MD Anderson experience in 174 patients.
    Gautam Borthakur, Farhad Ravandi, Keyur Patel, Xuemei Wang, Tapan Kadia, Courtney DiNardo, Guillermo Garcia-Manero, Naveen Pemmaraju, Elias Jabour, Koichi Takahashi, Maro Ohanian, Naval Daver, Yesid Alvarado, Mark Brandt, Sherry Pierce, Hagop Kantarjian.
      Fludarabine, cytarabine, GCSF (FLAG) based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO) (N=65) or in combination with idarubicin (FLAG-IDA) (N=109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59% respectively (p-value = 0.02). In multivariate analysis for RFS, age (p=0.0001), FLAG-GO regimen (p=0.04), 4 log reduction in CBF related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p=0.03) and additional cytogenetic abnormalities (p=0.03) were significant variables. Lower age (p=0.0001) and 3 log or more transcript reduction at end of induction p=0.04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p=0.06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p=0.002,), mid-consolidation (p<0.01) and end of consolidation (p<0.001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26700
  35. Leuk Res. 2022 Aug 23. pii: S0145-2126(22)00159-X. [Epub ahead of print]121 106933
    Acquired somatic variants confirm the independent development of AML in monozygotic twins with germline CEBPA variant.
    Helena Podgornik, Sandra Šućurović, Matevž Škerget, Maruša Debeljak, Samo Zver.
      
    DOI:  https://doi.org/10.1016/j.leukres.2022.106933
  36. Blood. 2022 Aug 29. pii: blood.2022016487. [Epub ahead of print]
    Chronic Conditions, Late Mortality and Health Status After Childhood AML: A Childhood Cancer Survivor Study Report.
    Lucie M Turcotte, Jillian A Whitton, Wendy M Leisenring, Rebecca Howell, Joseph P Neglia, Rachel Phelan, Kevin C Oeffinger, Kirsten K Ness, William Guard Woods, E Anders Kolb, Leslie L Robison, Gregory T Armstrong, Eric J Chow.
      Five-year survival following childhood acute myeloid leukemia (AML) has increased due to improvements in treatment and supportive care. The impact of these changes on long-term health outcomes is unknown. To address this, cumulative incidence of late mortality and grades 3-5 chronic health conditions (CHCs) standardized mortality ratios (SMR) were estimated among five-year AML survivors from the Childhood Cancer Survivor Study diagnosed 1970-1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT]; chemotherapy with cranial radiation [chemo+CRT]; chemotherapy only [chemo-only]) and decade of diagnosis. Self-reported health status was compared across treatments, decade of diagnosis, and with siblings. Among 856 survivors (median diagnosis age 7.1 years; median age at last follow-up 29.4 years) the 20-year late mortality cumulative incidence was highest after HCT (13.9%, 95%CI 10.0-17.8%; chemo+CRT 7.6%, 95%CI 2.2-13.1%; chemo-only 5.1%, 95%CI 2.8-7.4%). Mortality cumulative incidence decreased for survivors of HCT diagnosed in the 1990s (8.5%, 95%CI 4.1-12.8%) compared with the 1970s (38.9%, 95%CI 16.4-61.4%), as did SMRs. Most survivors did not experience any grade 3-5 CHC after 20 years (HCT, 45.8%; chemo+CRT 23.7%; chemo-only 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; p=0.02), mirroring a reduction in total body irradiation use. Self-reported health status was good to excellent for 88.2% of survivors, regardless of treatment; however, this was lower than siblings (94.8%; p<0.0001). Although HCT is associated with greater long-term morbidity and mortality compared with chemotherapy-based treatment, these gaps have narrowed and all treatment groups report favorable health status.
    DOI:  https://doi.org/10.1182/blood.2022016487
  37. Eur J Haematol. 2022 Aug 12.
    Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.
    Morten K Larsen, Vibe Skov, Lasse Kjaer, Natascha A Møller-Palacino, Rasmus K Pedersen, Morten Andersen, Johnny T Ottesen, Sabrina Cordua, Henrik E Poulsen, Morten Dahl, Trine A Knudsen, Christina Schjellerup Eickhardt-Dalbøge, Steffen Koschmieder, Kasper M Pedersen, Yunus Çolak, Stig E Bojesen, Børge G Nordestgaard, Thomas Stiehl, Hans C Hasselbalch, Christina Ellervik.
      The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)-adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m2 ) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil-to-lymphocyte ratio (NLR). We performed 11-year longitudinal follow-up of eGFR in all individuals. Compared to CHIP-negative individuals, the mean differences in eGFR were -5.6 (-10.3, -0.8, p = .02) for CALR, -11.9 (-21.4, -2.4, p = 0.01) for CALR type 2, and -10.1 (-18.1, -2.2, p = .01) for CALR with VAF ≥ 1%. The IPW-adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11-year longitudinal follow-up on eGFR compared to CHIP-negative individuals (p = .004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP-negative individuals as measured by a lower eGFR at baseline and during 11-year follow-up.
    Keywords:  CALR; CHIP; JAK2V617F; clonal haematopoiesis of indeterminate potential; eGFR; epidemiology; impaired kidney function; population studies
    DOI:  https://doi.org/10.1111/ejh.13845
  38. Am J Hematol. 2022 Aug 30.
    Postremission cytopenia management in patients with AML treated with venetoclax and azacitidine in VIALE-A.
    Keith W Pratz, Courtney D DiNardo, Dominik Selleslag, Junmin Li, Kazuhito Yamamoto, Marina Konopleva, Don Stevens, Hagop Kantarjian, Fabiola Traina, Adriano Venditti, Jiri Mayer, Melissa Montez, Huan Jin, Yinghui Duan, Deanna Brackman, Jiuhong Zha, Jalaja Potluri, Michael Werner, Brian A Jonas.
      
    DOI:  https://doi.org/10.1002/ajh.26692
  39. Sci Adv. 2022 Sep 02. 8(35): eabn9550
    In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
    Panayotis Pachnis, Zheng Wu, Brandon Faubert, Alpaslan Tasdogan, Wen Gu, Spencer Shelton, Ashley Solmonson, Aparna D Rao, Akash K Kaushik, Thomas J Rogers, Jessalyn M Ubellacker, Collette A LaVigne, Chendong Yang, Bookyung Ko, Vijayashree Ramesh, Jessica Sudderth, Lauren G Zacharias, Misty S Martin-Sandoval, Duyen Do, Thomas P Mathews, Zhiyu Zhao, Prashant Mishra, Sean J Morrison, Ralph J DeBerardinis.
      In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.
    DOI:  https://doi.org/10.1126/sciadv.abn9550
  40. EJHaem. 2022 Aug;3(3): 873-884
    The 17-gene stemness score associates with relapse risk and long-term outcomes following allogeneic haematopoietic cell transplantation in acute myeloid leukaemia.
    Dennis D H Kim, Igor Novitzky Basso, Taehyung Simon Kim, Seong Yoon Yi, Kyoung Ha Kim, Tracy Murphy, Steven Chan, Mark Minden, Ivan Pasic, Wilson Lam, Arjun Law, Fotios V Michelis, Armin Gerbitz, Auro Viswabandya, Jeffrey Lipton, Rajat Kumar, Stanley W K Ng, Tracy Stockley, Tong Zhang, Ian King, Jonas Mattsson, Jean C Y Wang.
      A 17-gene stemness (LSC17) score determines risk in acute myeloid leukaemia patients treated with standard chemotherapy regimens. The present study further analysed the impact of the LSC17 score at diagnosis on outcomes following allogeneic haematopoietic cell transplantation (HCT). Out of 452 patients with available LSC17 score, 123 patients received allogeneic HCT. Transplant outcomes, including overall (OS), leukaemia-free survival (LFS), relapse incidence (RI) and non-relapse mortality (NRM), were compared according to the LSC17 scored group. The patients with a low LSC17 score had higher OS (56.2%) and LFS (54.4%) at 2 years compared to patients with high LSC17 score (47.2%, p = 0.0237 for OS and 46.0%, p = 0.0181 for LFS). The low LSC17 score group also had a lower relapse rate at 2 years (12.7%) compared to 25.3% in the high LSC17 score group (p = 0.017), but no difference in NRM (p = 0.674). Worse outcomes in the high LSC17 score group for OS, LFS and relapse were consistently observed across all stratified sub-groups. The use of more intensive conditioning did not improve outcomes for either group. In contrast, chronic graft-versus-host-disease was associated with more favourable outcomes in both groups. The 17-gene stemness score is highly prognostic for survival and relapse risk following allogeneic HCT.
    Keywords:  AML; Acute leukaemia; Gene expression; LSC 17 score; Stem cell transplantation
    DOI:  https://doi.org/10.1002/jha2.466
  41. Nat Genet. 2022 Sep 01.
    The genomic landscape of pediatric acute lymphoblastic leukemia.
    Samuel W Brady, Kathryn G Roberts, Zhaohui Gu, Lei Shi, Stanley Pounds, Deqing Pei, Cheng Cheng, Yunfeng Dai, Meenakshi Devidas, Chunxu Qu, Ashley N Hill, Debbie Payne-Turner, Xiaotu Ma, Ilaria Iacobucci, Pradyuamna Baviskar, Lei Wei, Sasi Arunachalam, Kohei Hagiwara, Yanling Liu, Diane A Flasch, Yu Liu, Matthew Parker, Xiaolong Chen, Abdelrahman H Elsayed, Omkar Pathak, Yongjin Li, Yiping Fan, J Robert Michael, Michael Rusch, Mark R Wilkinson, Scott Foy, Dale J Hedges, Scott Newman, Xin Zhou, Jian Wang, Colleen Reilly, Edgar Sioson, Stephen V Rice, Victor Pastor Loyola, Gang Wu, Evadnie Rampersaud, Shalini C Reshmi, Julie Gastier-Foster, Jaime M Guidry Auvil, Patee Gesuwan, Malcolm A Smith, Naomi Winick, Andrew J Carroll, Nyla A Heerema, Richard C Harvey, Cheryl L Willman, Eric Larsen, Elizabeth A Raetz, Michael J Borowitz, Brent L Wood, William L Carroll, Patrick A Zweidler-McKay, Karen R Rabin, Leonard A Mattano, Kelly W Maloney, Stuart S Winter, Michael J Burke, Wanda Salzer, Kimberly P Dunsmore, Anne L Angiolillo, Kristine R Crews, James R Downing, Sima Jeha, Ching-Hon Pui, William E Evans, Jun J Yang, Mary V Relling, Daniela S Gerhard, Mignon L Loh, Stephen P Hunger, Jinghui Zhang, Charles G Mullighan.
      Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.
    DOI:  https://doi.org/10.1038/s41588-022-01159-z
  42. Cancer Res. 2022 Aug 30. pii: CAN-22-0985. [Epub ahead of print]
    Clonal hematopoiesis of indeterminate potential in patients with solid tumor malignancies.
    Catherine H Marshall, Lukasz P Gondek, Jun Luo, Emmanuel S Antonarakis.
      Clonal hematopoiesis of indeterminate potential (CHIP) refers to the expansion of cells of hematopoietic lineage that carry acquired somatic alterations associated with hematologic malignancies. The most commonly altered genes giving rise to CHIP are DNMT3A, TET2, and ASXL1. However, advanced sequencing technologies have resulted in highly sensitive detection of clonal hematopoiesis beyond these known driver genes. In practice, CHIP is commonly identified as an incidental finding in liquid and tissue biopsies of patients with solid tumors. CHIP can have broad clinical consequences, given its association with hematologic malignancies and non-malignant diseases. CHIP can also interfere with next-generation DNA sequencing results, so clinicians should pay careful attention when these results are being used to guide therapy. Future research is needed to determine how solid tumor malignancies and their treatments alter the progression of CHIP, and in turn, how CHIP might be used to improve treatment selection and outcomes for patients with solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0985
  43. Front Mol Biosci. 2022 ;9 959738
    A ferroptosis-related gene signature and immune infiltration patterns predict the overall survival in acute myeloid leukemia patients.
    Zhao Yin, Fang Li, Qinjun Zhou, Jianfang Zhu, Zhi Liu, Jing Huang, Huijuan Shen, Ruiming Ou, Yangmin Zhu, Qing Zhang, Shuang Liu.
      Targeted therapy for acute myeloid leukemia (AML) is an effective strategy, but currently, there are very limited therapeutic targets for AML treatment. Ferroptosis is strongly related to drug resistance and carcinogenesis. However, there are few reports about ferroptosis in AML. This article explores the relationship between ferroptosis-related gene (FRG) expression and prognosis in AML patients from the FerrDb and the Cancer Genome Atlas (TCGA) databases. The ferroptosis-related gene ARNTL was observed to have high expression and poor prognosis in AML. Receiver operating characteristic curve (ROC) analysis revealed the predictive accuracy of the signature. The area under the time-dependent ROC curve (AUC) was 0.533 at one year, 0.619 at two years, and 0.622 at three years within the training cohort. Moreover, we found that the ARNTL expression is closely associated with tumor-infiltrating immune cells like the macrophages and NK cells. Inhibiting the ARNTL expression suppressed colony formation and induced ferroptosis in AML cells. Overall, the survival prediction model constructed based on ARNTL accurately predicted the survival in AML patients, which could be a potential candidate for diagnosing and treating AML.
    Keywords:  AML; ARNTL; ferroptosis; immune cell infiltration; overall survival (OS)
    DOI:  https://doi.org/10.3389/fmolb.2022.959738
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