bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–02–04
35 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Prognostic Impact of Co-occurring Mutations in FLT3-ITD Pediatric Acute Myeloid Leukemia.
  2. Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.
  3. Real-World Analysis of Clinical Outcomes in AML, Myelodysplasia-Related: a Comparison of ICC and WHO-HAEM5 Criteria.
  4. Gilteritinib in combination with venetoclax, low-dose cytarabine and actinomycin D for relapsed or refractory FLT3-mutated acute myeloid leukaemia.
  5. Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.
  6. The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
  7. Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.
  8. Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia.
  9. Pim kinase inhibitors increase gilteritinib cytotoxicity in FLT3-ITD acute myeloid leukemia through GSK-3β activation and c-Myc and Mcl-1 proteasomal degradation.
  10. Myelodysplastic neoplasms evolving from inherited bone marrow failure syndromes / germline predisposition syndromes: Back under the microscope.
  11. Autophagy prevents graft failure during murine Graft versus Host Disease.
  12. Rapid and accurate remethylation of DNA in Dnmt3a-deficient hematopoietic cells with restoration of DNMT3A activity.
  13. Flow cytometry-based measurable residual disease (MRD) analysis identifies AML patients who may benefit from allogeneic hematopoietic stem cell transplantation.
  14. Cytogenetic and molecular associations with outcomes in HR-MDS treated with hypomethylating agents plus venetoclax.
  15. Single-Cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy.
  16. State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia.
  17. Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials.
  18. The prognostic impact of non-driver gene mutations and variant allele frequency in primary myelofibrosis.
  19. How we reduce and treat post-transplant relapse of MDS.
  20. Immortalised chronic myeloid leukemia (CML) derived mesenchymal stromal cells (MSCs) line retains the immunomodulatory and chemoprotective properties of CML patient-derived MSCs.
  21. KIT-mutated pediatric core-binding factor systemic mastocytosis-acute myeloid leukemia treated with avapritinib and decitabine.
  22. Calreticulin and JAK2V617F driver mutations induce distinct mitotic defects in myeloproliferative neoplasms.
  23. Phase 2 study of add-on parsaclisib in myelofibrosis patients with suboptimal response to ruxolitinib: Final results.
  24. Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
  25. BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia.
  26. A rare case of ICUS progressing to MDS with isolated isochromosome 17q and AML.
  27. Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.
  28. Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.
  29. Venous and Arterial Thrombosis in Patients with VEXAS Syndrome.
  30. Telomerase inhibitor imetelstat kills AML cells via lipid ROS and ferroptosis.
  31. A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.
  32. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
  33. Management of ALL in Adults: 2023 ELN Recommendations from a European Expert Panel.
  34. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
  35. Myelodysplastic syndromes del(5q): Pathogenesis and its therapeutic implications.
  1. Blood Adv. 2024 Jan 31. pii: bloodadvances.2023011980. [Epub ahead of print]
    Prognostic Impact of Co-occurring Mutations in FLT3-ITD Pediatric Acute Myeloid Leukemia.
    Katherine Tarlock, Robert B Gerbing, Rhonda E Ries, Jenny L Smith, Amanda R Leonti, Benjamin J Huang, Danielle C Kirkey, Leila Robinson, Jack H Peplinski, Beverly Lange, Todd M Cooper, Alan S Gamis, E Anders Kolb, Richard Aplenc, Jessica A Pollard, Soheil Meshinchi.
      We sought to define the co-occurring mutational profile of FLT3-ITD positive (ITDpos) acute myeloid leukemia (AML) in pediatric and young adult patients and to define the prognostic impact of cooperating mutations. We identified 464 patients with FLT3-ITD mutations treated on Children's Oncology Group trials with available sequencing and outcome data. Overall survival (OS), event-free survival (EFS), and relapse risk (RR) were determined according to the presence of co-occurring risk stratifying mutations. Among the cohort, 79% of patients had co-occurring alterations across 239 different genes that were altered through mutations or fusions. Evaluation of the prognostic impact of the co-occurring mutations demonstrated that ITDpos patients experienced significantly different outcomes according to the co-occurring mutational profile. ITDpos patients harboring a co-occurring favorable risk mutation (ITDFR) of NPM1, CEBPA, t(8;21), or inv(16) experienced a 5-year EFS of 64%, which was significantly superior to patients with ITDpos and poor risk mutations (ITDPR) of WT1, UBTF or NUP98::NSD1 of 22.2% as well as those that lacked either FR or PR mutation (ITDINT) of 40.9% (p<0.001 for both). Multivariable analysis demonstrated co-occurring mutations had significant prognostic impact, while allelic ratio had no impact. Therapy intensification, specifically consolidation transplant in remission resulted in significant improvements in survival for ITDpos AML. However, ITDpos/NUP98::NSD1 patients continued to have poor outcomes with intensified therapy, including sorafenib. Co-occurring mutational profile in ITDpos AML has significant prognostic impacts is critical to determining risk stratification and therapeutic allocation for ITDpos patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011980
  2. Haematologica. 2024 Feb 01.
    Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.
    Anmol Baranwal, Mark Gurney, Rami Basmaci, Bahga Katamesh, Rong He, David S Viswanatha, Patricia Greipp, James Foran, Talha Badar, Hemant Murthy, Cecilia Arana Yi, Jeanne Palmer, Abhishek A Mangaonkar, Mrinal M Patnaik, Mark R Litzow, William J Hogan, Kebede Begna, Naseema Gangat, Ayalew Tefferi, Aref Al-Kali, Mithun V Shah, Hassan B Alkhateeb.
      The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data is limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 comutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by ELN 2022 criteria (median OS 1.16 vs. 1.27 years, P = 0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P < 0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P = 0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P = 0.02), whereas melphalan-based conditioning was associated with a decreased relapse-risk (HR 0.02, P = 0.01). We conclude that mBCOR is a high-risk feature across MDS/AML and that alloSCT improves survival in this population.
    DOI:  https://doi.org/10.3324/haematol.2023.284185
  3. Blood Adv. 2024 Jan 29. pii: bloodadvances.2023011869. [Epub ahead of print]
    Real-World Analysis of Clinical Outcomes in AML, Myelodysplasia-Related: a Comparison of ICC and WHO-HAEM5 Criteria.
    Qianghua Zhou, Davidson Zhao, Morjgan Zarif, Marta B Davidson, Mark D Minden, Anne Tierens, Tony Yeung, Cuihong Wei, Hong Chang.
      The proposed 5th edition of the WHO classification of hematolymphoid tumors (WHO-HAEM5) and International Consensus Classification (ICC) employ different definitions of acute myeloid leukemia with myelodysplasia-related genetics (AML-MR). We conducted a retrospective study which included a cohort of 432 patients treated at our institution, with 354 WHO-AML-MR patients if classified according to WHO-HAEM5 or 276 ICC-AML-MR by gene mutation or cytogenetics (ICC-AML-MR-M/CG) patients if classified according to ICC. The clinicopathological features were similar, irrespective of the classification used, except for higher rates of complex karyotype, monosomy 17, TP53 mutations, and fewer RUNX1 mutations in the WHO-AML-MR group. TP53 mutations were associated with distinct clinicopathological features and dismal outcomes (hazard ratio [HR], 2.98; p < .001). ICC-AML-MR-M/CG group had superior outcome compared to the WHO-AML-MR group (HR 0.80, p = .032), mainly due to isolating out TP53 mutated AML to form a standalone entity. In the intensively treated group, WHO-AML-MR had significantly worse outcomes than AML by differentiation (HR: 1.97, p = .024). By ICC criteria, AML-MR defined by gene mutations or by cytogenetics had more inferior outcomes than AML not otherwise specified (HR: 2.11, p = .048 and HR: 2.55, p = .028; respectively). Furthermore, changing the order of defining AML-MR (i.e. by gene mutations or cytogenetics) did not significantly impact clinical outcomes. AML-MR defined by gene mutations or cytogenetic abnormalities showed similar outcomes regardless of the order of assignment (HR: 0.92, p = .73). We propose to harmonize the two classifications by excluding TP53 mutations from WHO-HAEM5 defined AML-MR group and combining AML-MR defined by gene mutations and cytogenetics to form a unified group.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011869
  4. Br J Haematol. 2024 Jan 30.
    Gilteritinib in combination with venetoclax, low-dose cytarabine and actinomycin D for relapsed or refractory FLT3-mutated acute myeloid leukaemia.
    Andrius Zucenka, Laimonas Griskevicius.
      We have conducted a retrospective, single-centre analysis of 20 patients with relapsed or refractory FLT3-mutated acute myeloid leukaemia (FLT3m AML) who received a salvage quadruplet regimen consisting of gilteritinib, venetoclax, low-dose cytarabine and actinomycin D (G-ACTIVE). G-ACTIVE resulted in a 95% (19/20) overall response rate and 75% (15/20) complete remission and complete remission with an incomplete platelet recovery (CR + CRp) rate. Out of 13 transplant-eligible patients, 11 (86%) proceeded to an allogeneic stem cell transplantation. The median overall survival and relapse-free survival after G-ACTIVE were 32 and 12.9 months respectively. The Day 60 mortality rate was 15%.
    Keywords:  AML; FLT3; acute leukaemia; allogeneic stem cell transplantation; gilteritinib; venetoclax
    DOI:  https://doi.org/10.1111/bjh.19318
  5. Cancer Res. 2024 Jan 29.
    Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.
    Andrew J Monteith, Haley E Ramsey, Alexander J Silver, Donovan Brown, Dalton Greenwood, Brianna N Smith, Ashley D Wise, Juan Liu, Sarah D Olmstead, Jackson Watke, Maria P Arrate, Agnieszka E Gorska, Londa Fuller, Jason W Locasale, Matthew C Stubbs, Jeffrey C Rathmell, Michael R Savona.
      Impairing the BET-family co-activator BRD4 with small molecule inhibitors (BETi) showed encouraging pre-clinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0291
  6. Blood Adv. 2024 Jan 31. pii: bloodadvances.2023010950. [Epub ahead of print]
    The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
    Marc Usart, Nils Hansen, Jan Stetka, Tiago Almeida Fonseca, Alexandre Guy, Quentin Kimmerlin, Shivam Rai, Hui Hao-Shen, Julien Roux, Stefan Dirnhofer, Radek C Skoda.
      Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, i.e. the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production. Consistently, in vivo treatment with CB-839 normalized blood glucose levels, reduced splenomegaly and decreased erythrocytosis in VF mice. These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when co-targeting different metabolic and oncogenic pathways. Furthermore, we show that the inhibition of glutaminolysis with CB-839 preferentially lowered the proportion of JAK2-mutant hematopoietic stem cells (HSCs). The total number of HSCs was decreased by CB-839, primarily by reducing HSCs in the G1 phase of the cell cycle. CB-839 in combination with ruxolitinib also strongly reduced myelofibrosis at later stages of MPN. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from PV patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting glutaminase alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010950
  7. Haematologica. 2024 Feb 01.
    Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.
    Akriti G Jain, Somedeb Ball, Luis Aguirre, Najla Al Ali, David Kaldas, Sara Tinsley-Vance, Andrew Kuykendall, Onyee Chan, Kendra Sweet, Jeffrey E Lancet, Eric Padron, David A Sallman, Rami Komrokji.
      The patterns of low risk myelodysplastic syndrome (MDS) progression, and the clinical and molecular features of those patterns are not well described. We divided our low risk (LR) MDS patients (n=1914) into 4 cohorts: 1) Patients who remained LR-MDS (LR-LR; n=1300; 68%), 2) Patients who progressed from LR to HR MDS (LR-HR) without AML transformation (n=317; 16.5%), 3) Patients who progressed from LR to HR MDS and then AML (LR-HR-AML; n=124; 6.5%), 4) Patients who progressed from LR MDS to AML directly (LR-AML; n=173; 9%). Risk factors for progression included male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin.
    DOI:  https://doi.org/10.3324/haematol.2023.283661
  8. Blood Adv. 2024 Feb 02. pii: bloodadvances.2023010805. [Epub ahead of print]
    Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia.
    Oussama Abla, Rhonda E Ries, Timothy J Triche, Robert B Gerbing, Betsy Hirsch, Susana Raimondi, Todd M Cooper, Jason E Farrar, Nathaniel Buteyn, Lauren M Harmon, Hong Wen, Aniruddha J Deshpande, Edward A Kolb, Alan S Gamis, Richard Aplenc, Todd Alonzo, Soheil Meshinchi.
      MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study from 2,080 children and young adults with AML registered on Children's Oncology Group (COG)-AAML0531 and AAML1031 trials. Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions:104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: two each of DDX3X and TEC, with six partners (DDX3Y, CEP164, SCN2B, TREH, NAP1L1 and XPO1) observed in single patients. Patients with MLLT10 (n=127) demonstrated adverse outcomes, with 5-year event-free survival (EFS) of 18.6% vs. 49% in non-MLLT10 patients (N=1953, P <0.001), inferior 5 year overall-survival (OS) of 38.2% vs. 65.7% (P ≤ 0.001) and a higher relapse risk of 76% vs 38.6% (P <0.001). Patients with KMT2A::MLLT10 had an EFS from study entry of 19.5% vs 12.7% (P=0.628), and an OS from study entry of 40.4% vs 27.6% (P=0.361) in those with other MLLT10 fusion partners. Patients with PICALM::MLLT10 had an EFS of 9.2% vs 20% in other MLLT10- without PICALM ( X::MLLT10) (P=0.788). Patients with PICALM::MLLT10 and X::MLLT10 fusions exhibit a DNA hypermethylation signature resembling NUP98::NSD1 fusions, while KMT2A::MLLT10 patients bear aberrations primarily affecting distal regulatory elements. Regardless of the fusion partner, patients with AML harboring MLLT10 fusions exhibit very high-risk features and should be prioritized for alternative therapeutic interventions. Clinical trials #NCT00372593 NCT01371981.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010805
  9. Cancer Res Commun. 2024 Jan 29.
    Pim kinase inhibitors increase gilteritinib cytotoxicity in FLT3-ITD acute myeloid leukemia through GSK-3β activation and c-Myc and Mcl-1 proteasomal degradation.
    Jonelle K Lee, Aditi Chatterjee, Mario Scarpa, Christopher M Bailey, Sandrine Niyongere, Prerna Singh, Moaath K Mustafa Ali, Shivani Kapoor, Yin Wang, Giovannino Silvestri, Maria R Baer.
      Acute myeloid leukemia (AML) with fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) has poor outcomes. FLT3-ITD drives constitutive and aberrant FLT3 signaling, activating STAT5 and upregulating the downstream oncogenic serine/threonine kinase Pim-1. FLT3 inhibitors are in clinical use, but with limited and transient efficacy. We previously showed that concurrent treatment with Pim and FLT3 inhibitors increases apoptosis induction in FLT3-ITD-expressing cells through post-translational downregulation of Mcl-1. Here we further elucidate the mechanism of action of this dual targeting strategy. Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. Pim inhibitor and gilteritinib co-treatment increased apoptosis induction, produced synergistic cytotoxicity, downregulated c-Myc protein expression, earlier than Mcl-1, increased turnover of both proteins, which was rescued by proteasome inhibition, and increased efficacy and prolonged survival in an in vivo model. Gilteritinib and Pim inhibitor co-treatment of Ba/F3-ITD cells infected with T58A c-Myc or S159A Mcl-1 plasmids, preventing phosphorylation at these sites, did not downregulate these proteins, increase their turnover or increase apoptosis induction. Moreover, concurrent treatment with gilteritinib and Pim inhibitors dephosphorylated (activated) the serine/threonine kinase glycogen synthase kinase-3β (GSK-3β), and GSK-3β inhibition prevented c-Myc and Mcl-1 downregulation and decreased apoptosis induction. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3β as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.  .
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0379
  10. Leuk Res. 2024 Jan 23. pii: S0145-2126(24)00007-9. [Epub ahead of print]137 107441
    Myelodysplastic neoplasms evolving from inherited bone marrow failure syndromes / germline predisposition syndromes: Back under the microscope.
    M Tarek Elghetany, Mrinal M Patnaik, Joseph D Khoury.
      Inherited bone marrow failure syndromes and germline predisposition syndromes (IBMFS/GPS) are associated with increased risk for hematologic malignancies, particularly myeloid neoplasms, such as myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The diagnosis of MDS in these syndromes poses difficulty due to frequent bone marrow hypocellularity and the presence of some degree of dysplastic features related to the underlying germline defect causing abnormal maturation of one or more cell lines. Yet, the diagnosis of MDS is usually associated with a worse outcome in several IBMFS/GPS. Criteria for the diagnosis of MDS in IBMFS/GPS have not been standardized with some authors suggesting a mixture of morphologic, cytogenetic, and genetic criteria. This review highlights these challenges and suggests a more standardized approach to nomenclature and diagnostic criteria.
    Keywords:  Bone marrow; Cytogenetics; Germline predisposition; Inherited bone marrow failure; Myelodysplastic syndrome clonal evolution
    DOI:  https://doi.org/10.1016/j.leukres.2024.107441
  11. Blood Adv. 2024 Jan 31. pii: bloodadvances.2023010972. [Epub ahead of print]
    Autophagy prevents graft failure during murine Graft versus Host Disease.
    Katie E Lineburg, Lucie Leveque-El Mouttie, Christopher R Hunter, Laeitia Le Texier, Crystal McGirr, Bianca Teal, Bruce R Blazar, Steven W Lane, Geoffrey R Hill, Jean-Pierre Levesque, Kelli P A MacDonald.
      Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and GVHD. We demonstrate in vitro that both TNF and IL-1β, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In an MHC mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic SCT and may represent a therapeutic target to prevent graft failure during GVHD.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010972
  12. Sci Adv. 2024 Feb 02. 10(5): eadk8598
    Rapid and accurate remethylation of DNA in Dnmt3a-deficient hematopoietic cells with restoration of DNMT3A activity.
    Yang Li, Haley J Abel, Michelle Cai, Taylor A LaValle, Tiankai Yin, Nichole M Helton, Amanda M Smith, Christopher A Miller, Timothy J Ley.
      Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of Dnmt3a or Dnmt3b (or both enzymes) or expressing the dominant-negative Dnmt3aR878H mutation [R882H in humans; the most common DNMT3A mutation found in acute myeloid leukemia (AML)]. Using these cells as substrates, we defined DNA remethylation after overexpressing wild-type (WT) DNMT3A1, DNMT3B1, DNMT3B3 (an inactive splice isoform of DNMT3B), or DNMT3L (a catalytically inactive "chaperone" for DNMT3A and DNMT3B in early embryogenesis). Overexpression of DNMT3A for 2 weeks reverses the hypomethylation phenotype of Dnmt3a-deficient cells or cells expressing the R878H mutation. Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of Dnmt3aR878H/+ marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele. DNMT3L reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function.
    DOI:  https://doi.org/10.1126/sciadv.adk8598
  13. Ann Hematol. 2024 Jan 30.
    Flow cytometry-based measurable residual disease (MRD) analysis identifies AML patients who may benefit from allogeneic hematopoietic stem cell transplantation.
    Josephine Lucero, Muhned Alhumaid, Igor Novitzky-Basso, Jose-Mario Capo-Chichi, Tracy Stockley, Vikas Gupta, Aniket Bankar, Steven Chan, Andre C Schuh, Mark Minden, Jonas Mattsson, Rajat Kumar, Hassan Sibai, Anne Tierens, Dennis D H Kim.
      Measurable residual disease (MRD) monitoring independently predicts long-term outcomes in patients with acute myeloid leukemia (AML). Of the various modalities available, multiparameter flow cytometry-based MRD analysis is widely used and relevant for patients without molecular targets. In the transplant (HCT) setting, the presence of MRD pre-HCT is associated with adverse outcomes. MRD-negative remission status pre-HCT was also associated with longer overall (OS) and progression-free survival and a lower risk of relapse. We hypothesize that the combination of disease risk and MRD at the time of first complete remission (CR1) could identify patients according to the benefit gained from HCT, especially for intermediate-risk patients. We performed a retrospective analysis comparing the outcomes of HCT versus non-HCT therapies based on MRD status in AML patients who achieved CR1. Time-dependent analysis was applied considering time-to-HCT as a time-dependent covariate and compared HCT versus non-HCT outcomes according to MRD status at CR1. Among 336 patients assessed at CR1, 35.1% were MRD positive (MRDpos) post-induction. MRDpos patients benefitted from HCT with improved OS and relapse-free survival (RFS), while no benefit was observed in MRDneg patients. In adverse-risk patients, HCT improved OS (HR for OS 0.55; p = 0.05). In intermediate-risk patients, HCT benefit was not significant for OS and RFS. Intermediate-risk MRDpos patients were found to have benefit from HCT with improved OS (HR 0.45, p = 0.04), RFS (HR 0.46, p = 0.02), and CIR (HR 0.41, p = 0.02). Our data underscore the benefit of HCT in adverse risk and MRDpos intermediate-risk AML patients.
    Keywords:  Acute myeloid leukemia; Allogeneic hematopoietic stem cell transplantation; Measurable residual disease; Risk-adapted treatment
    DOI:  https://doi.org/10.1007/s00277-024-05639-6
  14. Clin Cancer Res. 2024 Feb 01.
    Cytogenetic and molecular associations with outcomes in HR-MDS treated with hypomethylating agents plus venetoclax.
    Alexandre Bazinet, Sai Prasad Desikan, Ziyi Li, Juan Jose Rodriguez-Sevilla, Sangeetha Venugopal, Samuel Urrutia, Guillermo Montalban-Bravo, Koji Sasaki, Kelly S Chien, Danielle Hammond, Rashmi Kanagal-Shamanna, Irene Ganan-Gomez, Tapan M Kadia, Gautam Borthakur, Courtney D DiNardo, Naval G Daver, Elias J Jabbour, Farhad Ravandi, Hagop Kantarjian, Guillermo Garcia-Manero.
       PURPOSE: Hypomethylating agents (HMAs) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood.
    EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes.
    RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes.
    CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2860
  15. Cancer Res Commun. 2023 Feb 01.
    Single-Cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy.
    Ignacio Campillo-Marcos, Marta Casado-Pelaez, Veronica Davalos, Gerardo Ferrer, Caterina Mata, Elisabetta Mereu, Gael Roue, David Valcárcel, Antonieta Molero, Lurdes Zamora, Blanca Xicoy, Laura Palomo, Pamela Acha, Ana Manzanares, Magnus Tobiasson, Eva Hellström-Lindberg, Francesc Sole, Manel Esteller.
      Alterations in epigenetic marks, such as DNA methylation, represent a hallmark of cancer that has been successfully exploited for therapy in myeloid malignancies. Hypomethylating agents (HMAs), such as azacitidine (AZA), have become standard-of-care therapy to treat myelodysplastic syndromes (MDS), a myeloid neoplasms that can evolve into acute myeloid leukemia (AML). However, our capacity to identify who will respond to HMAs, and the duration of response, remains limited. To shed light on this question, we have leveraged the unprecedented analytical power of single-cell technologies to simultaneously map the genome and immunoproteome of MDS samples throughout clinical evolution. We were able to chart the architecture and evolution of molecular clones in precious paired bone marrow MDS samples at diagnosis and post-treatment to show that a combined imbalance of specific cell lineages with diverse mutational profiles is associated with the clinical response of MDS patients to hypomethylating therapy.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0389
  16. Leukemia. 2024 Feb 02.
    State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia.
    David E Frankhouser, Russell C Rockne, Lisa Uechi, Dandan Zhao, Sergio Branciamore, Denis O'Meally, Jihyun Irizarry, Lucy Ghoda, Haris Ali, Jeffery M Trent, Stephen Forman, Yu-Hsuan Fu, Ya-Huei Kuo, Bin Zhang, Guido Marcucci.
      Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape. The potential's stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention, before phenotypic changes become detectable.
    DOI:  https://doi.org/10.1038/s41375-024-02142-9
  17. Leukemia. 2024 Jan 29.
    Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials.
    Elias Jabbour, Jane Apperley, Jorge Cortes, Delphine Rea, Michael Deininger, Elisabetta Abruzzese, Charles Chuah, Daniel J DeAngelo, Andreas Hochhaus, Jeffrey H Lipton, Michael Mauro, Franck Nicolini, Javier Pinilla-Ibarz, Gianantonio Rosti, Philippe Rousselot, Neil P Shah, Moshe Talpaz, Alexander Vorog, Xiaowei Ren, Hagop Kantarjian.
      Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.
    DOI:  https://doi.org/10.1038/s41375-024-02159-0
  18. Am J Hematol. 2024 Jan 30.
    The prognostic impact of non-driver gene mutations and variant allele frequency in primary myelofibrosis.
    Spanish MPN Group (GEMFIN)
      Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.
    DOI:  https://doi.org/10.1002/ajh.27203
  19. Blood. 2024 Feb 02. pii: blood.2023023005. [Epub ahead of print]
    How we reduce and treat post-transplant relapse of MDS.
    Alain Mina, Peter L Greenberg, H Joachim Deeg.
      Allogeneic hematopoietic stem cell transplant (HSCT) is the only potentially curative option for patients with high-risk myelodysplastic syndromes (MDS). Advances in conditioning regimens and supportive measures have reduced treatment-related mortality and increased the role of transplantation, leading to more patients undergoing HSCT. However, post-transplant relapse of MDS remains a leading cause of morbidity and mortality for this procedure necessitating expert management and ongoing results analysis. In this article, we review treatment options and our institutional approaches to managing MDS relapse after HSCT using illustrative clinical cases that exemplify different clinical manifestations and management of relapse. We address areas of controversy relating to conditioning regimen intensity, chemotherapeutic bridging, and donor selection. In addition, we discuss future directions for advancing the field, including (1) the need for prospective clinical trials separating MDS from AML and focusing on post-transplant relapse, as well as (2) the validation of measurable residual disease methodologies to guide timely interventions.
    DOI:  https://doi.org/10.1182/blood.2023023005
  20. Cell Signal. 2024 Jan 27. pii: S0898-6568(24)00035-4. [Epub ahead of print]116 111067
    Immortalised chronic myeloid leukemia (CML) derived mesenchymal stromal cells (MSCs) line retains the immunomodulatory and chemoprotective properties of CML patient-derived MSCs.
    Esther Sathya Bama Benjamin, Elizabeth Vinod, Raveen Stephen Stallon Illangeswaran, Bharathi M Rajamani, Rakhi Thalayattu Vidhyadharan, Abhirup Bagchi, Arnab Maity, Ajith Mohan, Ganesh Parasuraman, Soosai Manickam Amirtham, Aby Abraham, Shaji R Velayudhan, Poonkuzhali Balasubramanian.
      Despite the success of Tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), leukemic stem cells (LSCs) persist, contributing to relapse and resistance. CML Mesenchymal Stromal Cells (MSCs) help in LSC maintenance and protection from TKIs. However, the limited passage and self-differentiation abilities of primary CML MSCs hinder extensive research. To overcome this, we generated and characterized an immortalised CML patient-derived MSC (iCML MSC) line and assessed its role in LSC maintenance. We also compared the immunophenotype and differentiation potential between primary CML MSCs at diagnosis, post-treatment, and with normal bone marrow MSCs. Notably, CML MSCs exhibited enhanced chondrogenic differentiation potential compared to normal MSCs. The iCML MSC line retained the trilineage differentiation potential and was genetically stable, enabling long-term investigations. Functional studies demonstrated that iCML MSCs protected CML CD34+ cells from imatinib-induced apoptosis, recapitulating the bone marrow microenvironment-mediated resistance observed in patients. iCML MSC-conditioned media enabled CML CD34+ and AML blast cells to proliferate rapidly, with no impact on healthy donor CD34+ cells. Gene expression profiling revealed dysregulated genes associated with calcium metabolism in CML CD34+ cells cocultured with iCML MSCs, providing insights into potential therapeutic targets. Further, cytokine profiling revealed that the primary CML MSC lines abundantly secreted 25 cytokines involved in immune regulation, supporting the hypothesis that CML MSCs create an immune modulatory microenvironment that promotes growth and protects against TKIs. Our study establishes the utility of iCML MSCs as a valuable model to investigate leukemic-stromal interactions and study candidate genes involved in mediating TKI resistance in CML LSCs.
    Keywords:  Chronic myeloid leukemia; Leukemic stem cells; Mesenchymal stromal cells; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111067
  21. Pediatr Blood Cancer. 2024 Jan 30. e30898
    KIT-mutated pediatric core-binding factor systemic mastocytosis-acute myeloid leukemia treated with avapritinib and decitabine.
    Irtiza N Sheikh, Shaikha AlQahtani, C Cameron Yin, David McCall, Branko Cuglievan, Dristhi Ragoonanan, Jeremy S Connors, Amber Gibson, Cesar Nunez, Michael Roth, Maro Ohanian, Gautam Borthakur, Miriam B Garcia.
      
    DOI:  https://doi.org/10.1002/pbc.30898
  22. Sci Rep. 2024 Feb 02. 14(1): 2810
    Calreticulin and JAK2V617F driver mutations induce distinct mitotic defects in myeloproliferative neoplasms.
    Kristin Holl, Nicolas Chatain, Susanne Krapp, Julian Baumeister, Tiago Maié, Sarah Schmitz, Anja Scheufen, Nathalie Brock, Steffen Koschmieder, Daniel Moreno-Andrés.
      Myeloproliferative neoplasms (MPNs) encompass a diverse group of hematologic disorders driven by mutations in JAK2, CALR, or MPL. The prevailing working model explaining how these driver mutations induce different disease phenotypes is based on the decisive influence of the cellular microenvironment and the acquisition of additional mutations. Here, we report increased levels of chromatin segregation errors in hematopoietic cells stably expressing CALRdel52 or JAK2V617F mutations. Our investigations employing murine 32DMPL and human erythroleukemic TF-1MPL cells demonstrate a link between CALRdel52 or JAK2V617F expression and a compromised spindle assembly checkpoint (SAC), a phenomenon contributing to error-prone mitosis. This defective SAC is associated with imbalances in the recruitment of SAC factors to mitotic kinetochores upon CALRdel52 or JAK2V617F expression. We show that JAK2 mutant CD34 + MPN patient-derived cells exhibit reduced expression of the master mitotic regulators PLK1, aurora kinase B, and PP2A catalytic subunit. Furthermore, the expression profile of mitotic regulators in CD34 + patient-derived cells allows to faithfully distinguish patients from healthy controls, as well as to differentiate primary and secondary myelofibrosis from essential thrombocythemia and polycythemia vera. Altogether, our data suggest alterations in mitotic regulation as a potential driver in the pathogenesis in MPN.
    DOI:  https://doi.org/10.1038/s41598-024-53240-8
  23. Blood Adv. 2024 Jan 30. pii: bloodadvances.2023011620. [Epub ahead of print]
    Phase 2 study of add-on parsaclisib in myelofibrosis patients with suboptimal response to ruxolitinib: Final results.
    Abdulraheem Yacoub, Uma Borate, Raajit K Rampal, Haris Ali, Eunice S Wang, Aaron T Gerds, Gabriela Soriano Hobbs, Marina Kremyanskaya, Elliott F Winton, Casey O'Connell, Swati Goel, Stephen T Oh, Gary J Schiller, James McCloskey, Jeanne M Palmer, Houston Holmes, Steven Hager, Albert Assad, Susan Erickson-Viitanen, Feng Zhou, Naval G Daver.
      Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib in patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg once daily for 8 weeks, then once weekly thereafter (daily-to-weekly dosing; n=32), or parsaclisib 5 or 20 mg once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n=42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in MFSAF or MPN-SAF symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011620
  24. Nat Commun. 2024 Jan 27. 15(1): 828
    Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
    Rani Pallavi, Elena Gatti, Tiphanie Durfort, Massimo Stendardo, Roberto Ravasio, Tommaso Leonardi, Paolo Falvo, Bruno Achutti Duso, Simona Punzi, Aobuli Xieraili, Andrea Polazzi, Doriana Verrelli, Deborah Trastulli, Simona Ronzoni, Simone Frascolla, Giulia Perticari, Mohamed Elgendy, Mario Varasi, Emanuela Colombo, Marco Giorgio, Luisa Lanfrancone, Saverio Minucci, Luca Mazzarella, Pier Giuseppe Pelicci.
      Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR's impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.
    DOI:  https://doi.org/10.1038/s41467-023-44348-y
  25. Cancer Sci. 2024 Jan 30.
    BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia.
    Jianwei Liu, Tomoya Isaji, Sachiko Komatsu, Yuhan Sun, Xing Xu, Tomohiko Fukuda, Tsutomu Fujimura, Shinichiro Takahashi, Jianguo Gu.
      Fms-like tyrosine kinase-3 (FLT3) is a commonly mutated gene in acute myeloid leukemia (AML). The two most common mutations are the internal-tandem duplication domain (ITD) mutation and the tyrosine kinase domain (TKD) mutation. FLT3-ITD and FLT3-TKD exhibit distinct protein stability, cellular localization, and intracellular signaling. To understand the underlying mechanisms, we performed proximity labeling with TurboID to identify proteins that regulate FLT3-ITD or -TKD differently. We found that BRCA1/BRCA2-containing complex subunit 36 (BRCC36), a specific K63-linked polyubiquitin deubiquitinase, was exclusively associated with ITD, not the wild type of FLT3 and TKD. Knockdown of BRCC36 resulted in decreased signal transducers and activators of transcription 5 phosphorylation and cell proliferation in ITD cells. Consistently, treatment with thiolutin, an inhibitor of BRCC36, specifically suppressed cell proliferation and induced cell apoptosis in ITD cells. Thiolutin efficiently affected leukemia cell lines expressing FLT3-ITD cell viability and exhibited mutual synergies with quizartinib, a standard clinical medicine for AML. Furthermore, mutation of the lysine at 609 of ITD led to significant suppression of K63 polyubiquitination and decreased its stability, suggesting that K609 is a critical site for K63 ubiquitination specifically recognized by BRCC36. These data indicate that BRCC36 is a specific regulator for FLT3-ITD, which may shed light on developing a novel therapeutic approach for AML.
    Keywords:  N-glycan; cellular signaling; deubiquitination; glycoprotein; protein stability
    DOI:  https://doi.org/10.1111/cas.16090
  26. Blood. 2024 Feb 01. 143(5): 473
    A rare case of ICUS progressing to MDS with isolated isochromosome 17q and AML.
    Eva Elisa Ordonez Mazariegos, Yiannis Petros Dimopoulos.
      
    DOI:  https://doi.org/10.1182/blood.2023022678
  27. Sci Adv. 2024 Feb 02. 10(5): eadj9479
    Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.
    Adam G Maynard, Nancy K Pohl, Annabel P Mueller, Boryana Petrova, Alan Y L Wong, Peng Wang, Andrew J Culhane, Jeannette R Brook, Leah M Hirsch, Ngoc Hoang, Orville Kirkland, Tatum Braun, Sarah Ducamp, Mark D Fleming, Hojun Li, Naama Kanarek.
      Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.
    DOI:  https://doi.org/10.1126/sciadv.adj9479
  28. Leukemia. 2024 Jan 31.
    Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.
    A A van de Loosdrecht, E M P Cremers, C Alhan, C Duetz, F E M In 't Hout, H A Visser-Wisselaar, D A Chitu, A Verbrugge, S M Cunha, G J Ossenkoppele, J J W M Janssen, S K Klein, E Vellenga, G A Huls, P Muus, S M C Langemeijer, G E de Greef, P A W Te Boekhorst, M H G Raaijmakers, M van Marwijk Kooy, M C Legdeur, J J Wegman, W Deenik, O de Weerdt, T M van Maanen-Lamme, P Jobse, R J W van Kampen, A Beeker, P W Wijermans, B J Biemond, B C Tanis, J W J van Esser, C G Schaar, H S Noordzij-Nooteboom, E M G Jacobs, A O de Graaf, M Jongen-Lavrencic, M J P L Stevens-Kroef, T M Westers, J H Jansen.
      A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).
    DOI:  https://doi.org/10.1038/s41375-024-02161-6
  29. Blood. 2024 Feb 02. pii: blood.2023022329. [Epub ahead of print]
    Venous and Arterial Thrombosis in Patients with VEXAS Syndrome.
    Yael Kusne, Atefeh Ghorbanzadeh, Alina Dulau Florea, Ruba N Shalhoub, Pedro Emilio Alcedo Andrade, Khanh Nghiem, Marcela A Ferrada, Alexander Hines, Kaitlin A Quinn, Sumith R Panicker, Amanda K Ombrello, Kaaren K Reichard, Ivana Darden, Wendy Goodspeed, Jibran Durrani, Lorena Wilson, Horatiu Olteanu, Terra L Lasho, Daniel L Kastner, Kenneth J Warrington, Abhishek A Mangaonkar, Ronald S Go, Raul C Braylan, David B Beck, Mrinal M Patnaik, Neal S Young, Katherine R Calvo, Ana Casanegra, Peter C Grayson, Matthew J Koster, Colin O Wu, Yogendra Kanthi, Bhavisha A Patel, Damon E Houghton, Emma M Groarke.
      VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS. The risks factors and frequency of thrombosis in VEXAS are not well described, due to the disease's new discovery and paucity of large databases. We evaluated 119 VEXAS patients for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two thirds of VTE were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence (CI) of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism (PE) by univariate (OR: 4.58, CI 1.28-16.21; p=0.02) and multivariate (OR: 16.94, CI 1.99-144.3; p=0.01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival (OS) of the entire patient cohort at median follow up time of 4.8 years was 88% and there was no difference in survival between patients with or without thrombosis (p=0.8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.
    DOI:  https://doi.org/10.1182/blood.2023022329
  30. Nat Cancer. 2024 Jan;5(1): 12-13
    Telomerase inhibitor imetelstat kills AML cells via lipid ROS and ferroptosis.
      
    DOI:  https://doi.org/10.1038/s43018-023-00654-4
  31. PLoS One. 2024 ;19(1): e0292375
    A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.
    Tingting Huang, Bernice Leung, Yuyang Huang, Laura Price, Jiang Gui, Bonnie W Lau.
      Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.
    DOI:  https://doi.org/10.1371/journal.pone.0292375
  32. Science. 2024 Feb 02. 383(6682): eadi5798
    Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
    Skye Montoya, Jessie Bourcier, Mark Noviski, Hao Lu, Meghan C Thompson, Alexandra Chirino, Jacob Jahn, Anya K Sondhi, Stefan Gajewski, Ying Siow May Tan, Stephanie Yung, Aleksandra Urban, Eric Wang, Cuijuan Han, Xiaoli Mi, Won Jun Kim, Quinlan Sievers, Paul Auger, Hugo Bousquet, Nivetha Brathaban, Brandon Bravo, Melissa Gessner, Cristiana Guiducci, James N Iuliano, Tim Kane, Ratul Mukerji, Panga Jaipal Reddy, Janine Powers, Mateo Sanchez Garcia de Los Rios, Jordan Ye, Carla Barrientos Risso, Daniel Tsai, Gabriel Pardo, Ryan Q Notti, Alejandro Pardo, Maurizio Affer, Vindhya Nawaratne, Tulasigeri M Totiger, Camila Pena-Velasquez, Joanna M Rhodes, Andrew D Zelenetz, Alvaro Alencar, Lindsey E Roeker, Sanjoy Mehta, Ralph Garippa, Adam Linley, Rajesh Kumar Soni, Sigrid S Skånland, Robert J Brown, Anthony R Mato, Gwenn M Hansen, Omar Abdel-Wahab, Justin Taylor.
      Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.
    DOI:  https://doi.org/10.1126/science.adi5798
  33. Blood. 2024 Feb 02. pii: blood.2023023568. [Epub ahead of print]
    Management of ALL in Adults: 2023 ELN Recommendations from a European Expert Panel.
    Nicola Gökbuget, Nicolas Boissel, Sabina Chiaretti, Herve Dombret, Michael Doubek, Adele K Fielding, Robin Foà, Sebastian Giebel, Dieter Hoelzer, Mathilde Hunault, David I Marks, Giovanni Martinelli, Oliver Ottmann, Anita W Rijneveld, Philippe Rousselot, Josep-Maria Ribera, Renato Bassan.
      Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult ALL from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors and assessment of ALL (cross-reference). The current recommendation summarizes clinical management. It covers treatment approaches including the use of new immunotherapies, application of MRD for treatment decisions, management of specific subgroups and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult ALL patients which has to be complemented by regional expertise preferably provided by national academic study groups.
    DOI:  https://doi.org/10.1182/blood.2023023568
  34. Nature. 2024 Jan 31.
    7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
    Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira Dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M Lorenz, Viktoria Kunz, Helene Nehring, Thamara N Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G Doll, Emily L Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M Wehman, Thiago C Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B Sathian, David B Konrad, Douglas F Covey, Bernhard Michalke, Kurt Bommert, Ralf C Bargou, Ana Garcia-Saez, Derek A Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad, José Pedro Friedmann Angeli.
      Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
    DOI:  https://doi.org/10.1038/s41586-023-06878-9
  35. Eur J Haematol. 2024 Jan 31.
    Myelodysplastic syndromes del(5q): Pathogenesis and its therapeutic implications.
    Antonella Bruzzese, Enrica Antonia Martino, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Isabella Capodanno, Antonino Neri, Fortunato Morabito, Ernesto Vigna, Massimo Gentile.
      Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as "myelodysplastic neoplasm with low blast and isolated del(5q)" identified by the sole presence of 5q deletion or in combination with one other abnormality excluding -7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression.
    Keywords:  MDS-5q; TP53 mutation; chromosome 5; common deleted regions; lenalidomide; myelodysplastic syndromes; myeloid neoplasm
    DOI:  https://doi.org/10.1111/ejh.14181
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