bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–02–23
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Clinical-genomic profiling of MDS to inform allo-HSCT:Recommendations from an international panel on behalf of the EBMT.
  2. PSPC1 exerts an oncogenic role in AML by regulating a leukemic transcription program in cooperation with PU.1.
  3. Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML::RARα.
  4. Characteristics and Survival of Secondary Acute Myeloid Leukemia From Myelodysplastic Syndromes in Older Adults: A Population Analysis.
  5. Assessing AML-based risk criteria in patients with accelerated/blast-phase MPN treated with less-intensive therapy.
  6. Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia.
  7. Maintenance Therapy in AML: What Is the Future Potential?
  8. Immune-deficient MISTRG mice support expansion of leukaemia-initiating cells in xenograft models of paediatric acute myeloid leukaemia.
  9. Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease.
  10. Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98 -rearranged leukemia.
  11. A phase II trial of azacitidine with ipilimumab, nivolumab, or ipilimumab and nivolumab in previously untreated myelodysplastic syndrome.
  12. Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations.
  13. Preconditioning intervention before allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia.
  14. Proteomic Comparison of Acute Myeloid Leukemia Cells and Normal CD34+ Bone Marrow Cells: Studies of Leukemia Cell Differentiation and Regulation of Iron Metabolism/Ferroptosis.
  15. Improved Outcome and Therapeutic Directions in Pediatric Therapy-related AML: Recommendations by the AML-BFM Study Group.
  16. CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia.
  17. Venetoclax in combination with hypomethylating agents in newly diagnosed and relapsed CBFβ::MYH11+ acute myeloid leukemia.
  18. Oral iptacopan for paroxysmal nocturnal haemoglobinuria-First real-world experience.
  19. Single Cell Spatial Transcriptomics Reveals Immunotherapy-Driven Bone Marrow Niche Remodeling in AML.
  20. Frontline Therapy of AML in the Fit and Younger Population-Incorporating Molecularly Targeted Agents.
  21. Cooperative nutrient scavenging is an evolutionary advantage in cancer.
  22. Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome.
  1. Blood. 2025 Feb 19. pii: blood.2024025131. [Epub ahead of print]
    Clinical-genomic profiling of MDS to inform allo-HSCT:Recommendations from an international panel on behalf of the EBMT.
    Carmelo Gurnari, Marie Robin, Lionel Adès, Mahmoud Aljurf, Antonio M Almeida, Fernando Barroso Duarte, Elsa Bernard, Corey S Cutler, Matteo Giovanni Della Porta, Theo M de Witte, Amy E DeZern, Joanna Drozd-Sokolowska, Eric J Duncavage, Pierre Fenaux, Nico Gagelmann, Guillermo Garcia-Manero, Claudia Haferlach, Torsten Haferlach, Robert P Hasserjian, Eva S Hellstrom-Lindberg, Meagan A Jacoby, Austin G Kulasekararaj, R Coleman Lindsley, Jaroslaw P Maciejewski, Hideki Makishima, Luca Malcovati, Moshe Mittelman, Anders Eivind Myhre, Seishi Ogawa, Francesco Onida, Elli Papaemmanuil, Jakob R Passweg, Uwe Platzbecker, Lisa Pleyer, Kavita Raj, Valeria Santini, Anna Sureda, Magnus Tobiasson, Maria Teresa Voso, Ibrahim Yakoub-Agha, Amer M Zeidan, Matthew J Walter, Nicolaus Kröger, Donal P McLornan, Mario Cazzola.
      For patients with myelodysplastic neoplasm/syndrome (MDS), allogeneic hematopoietic cell transplantation (allo-HCT) represents the only potentially curative treatment, capable of eradicating disease-related mutant hematopoietic cells and establishing normal donor hematopoiesis. Biologic-assignment clinical trials have indicated that in eligible patients, allo-HCT is associated with superior clinical outcomes compared to non-transplant therapy. However, this therapeutic option is only available to a subset of patients, and the outcome is influenced by multiple factors inherent to the patient, the MDS subtype, and the allo-HCT procedure itself. In 2017, the EBMT published recommendations for allo-HCT in MDS to guide practical decision-making. In the contemporary era, genomic profiling has become routine clinical practice in many centers, and the most recent classification systems include MDS entities that are defined by genetic abnormalities. In particular, the Molecular International Prognostic Scoring System (IPSS-M) offers more precise prognostication across all clinical endpoints and currently represents the standard tool for estimating patient survival in the absence of disease-modifying treatment. Evidence from multiple sources increasingly indicates that allo-HCT should be considered at the time of diagnosis in all eligible MDS patients. Therefore, genomic profiling for somatic mutations and testing for germline predisposition variants are integral to determining a patient's eligibility for transplantation. While all patients with higher-risk MDS are potential candidates for immediate transplantation, a subset of those with lower-risk MDS may also derive benefit from this procedure at an earlier disease stage. Comprehensive recommendations on behalf of an expert international panel for clinical practice and future clinical studies of relevance are presented.
    DOI:  https://doi.org/10.1182/blood.2024025131
  2. Cell Stem Cell. 2025 Feb 12. pii: S1934-5909(25)00010-4. [Epub ahead of print]
    PSPC1 exerts an oncogenic role in AML by regulating a leukemic transcription program in cooperation with PU.1.
    Juyeong Hong, Pinpin Sui, Ying Li, Kerryn Y Xu, Ji-Hoon Lee, Juan Wang, Shi Chen, Peng Zhang, Noah Wingate, Asra Noor, Yaxia Yuan, Robert Hromas, Hongwei Zhou, Karina Hamamoto, Rui Su, C Cameron Yin, Fengxi Ye, Andrés E Quesada, Jianjun Chen, Suming Huang, Daohong Zhou, M James You, Feng-Chun Yang, Jianlong Wang, Mingjiang Xu.
      Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy characterized by the blockage of myeloid cell differentiation and uncontrolled proliferation of immature myeloid cells. Here, we show that paraspeckle component 1 (PSPC1) is aberrantly overexpressed and associated with poor survival in AML patients. Using human AML cells and mouse models, we demonstrate that PSPC1 is not required for normal hematopoiesis, but it is critical and essential for AML cells to maintain their leukemic characteristics. PSPC1 loss induces robust differentiation, suppresses proliferation, and abolishes leukemogenesis in diverse AML cells. Mechanistically, PSPC1 exerts a pro-leukemia effect by regulating a unique leukemic transcription program via cooperative chromatin binding with PU.1 and activation of tumor-promoting genes, including NDC1, which is not previously implicated in AML. Our findings uncover a unique and crucial role of PSPC1 dependency in AML and highlight its potential as a promising therapeutic target for AML.
    Keywords:  AML; NDC1; PSPC1; PU.1; hematopoiesis; leukemia
    DOI:  https://doi.org/10.1016/j.stem.2025.01.010
  3. Leukemia. 2025 Feb 20.
    Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML::RARα.
    Mariko Minami, Teppei Sakoda, Gentaro Kawano, Yu Kochi, Kensuke Sasaki, Takeshi Sugio, Fumiaki Jinnouchi, Kohta Miyawaki, Yuya Kunisaki, Koji Kato, Toshihiro Miyamoto, Koichi Akashi, Yoshikane Kikushige.
      Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34+CD38- fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (PML::RARα) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the PML gene, concentrate in the CD34+CD38- fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34+CD38-TIM-3+ short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34- differentiated APL cells did not. Furthermore, CD34+CD38-TIM-3+ short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.
    DOI:  https://doi.org/10.1038/s41375-025-02530-9
  4. Clin Lymphoma Myeloma Leuk. 2025 Jan 23. pii: S2152-2650(25)00023-0. [Epub ahead of print]
    Characteristics and Survival of Secondary Acute Myeloid Leukemia From Myelodysplastic Syndromes in Older Adults: A Population Analysis.
    Akshee Batra, Andrew Sparks, Rohit Singh, Neil A Zakai, Diego Adrianzen Herrera.
       BACKGROUND: Acute myeloid leukemia (AML) arising from myelodysplastic syndromes (MDS) is a unique subtype of secondary AML (sAML) with poor prognosis. We defined its epidemiologic profile in older adults.
    METHODS: Using the SEER-Medicare database, we identified MDS cases that progressed to AML between 2007 and 2017, during the era of hypomethylating agents (HMA). Established algorithms determined demographics, MDS histology, MDS risk by Simplified Myelodysplastic Syndrome Risk Score (SMMRS), comorbidity, transfusion burden, and HMA therapy. We defined overall survival (OS) after sAML, and examined factors associated with AML and mortality, including the impact of prior HMA therapy.
    RESULTS: Of 15,227 MDS patients, 12.3% developed AML. Incidence varied by MDS histology and SMMRS. Time to AML was shorter with higher SMMRS. Older age and higher comorbidity were associated with lower odds of AML. Higher SMMRS (OR = 2.5, 95CI: 2.0-3.0), transfusion dependence (OR = 2.6, 95CI: 2.1-3.2), and HMA use (OR = 4.9, 95CI: 4.4-5.5) were associated with increased transformation risk. Median OS after AML diagnosis was 3 months. OS rates at 1 and 2 years were 25% and 12%. Survival varied by antecedent MDS histology, being longest in those with ringed sideroblasts (P < .001). Older age (HR = 1.4, 95CI: 1.1-1.9) and higher SMMRS (HR = 1.8, 95CI: 1.5-2.2) were associated with risk of death. Antecedent HMA exposure was associated with longer OS (4 vs. 2 months, P < .01), with 4 or more HMA cycles associated with decreased risk of death (HR = 0.53, 95CI: 0.47-0.60).
    CONCLUSION: Risk of sAML is significant even in lower-risk MDS histologies. Survival is poor and varies by antecedent MDS characteristics. HMA exposure association with longer survival warrants further analysis.
    Keywords:  Epidemiology; Hypomethylating agents; SEER Program; Simplified Myelodysplastic Syndrome Risk Score; Transfusion burden
    DOI:  https://doi.org/10.1016/j.clml.2025.01.012
  5. Blood Adv. 2025 Feb 19. pii: bloodadvances.2024015712. [Epub ahead of print]
    Assessing AML-based risk criteria in patients with accelerated/blast-phase MPN treated with less-intensive therapy.
    Reid Shaw, James J Yoon, Hannah Johnston, Marta B Davidson, Alexa J Siddon, Rory M Shallis, Evan Chris Chen, Madelyn Burkart, Timothy S Oh, Sunil Girish Iyer, Ellen Madarang, Chandrasekar Muthiah, Joshua Kassner, Raajit K Rampal, Guru Subramanian Guru Murthy, Terrence J Bradley, Yasmin Abaza, Jacqueline S Garcia, Vikas Gupta, Kristen M Pettit, Olatoyosi Odenike, Anand A Patel.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024015712
  6. Leukemia. 2025 Feb 15.
    Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia.
    Sameem M Abedin, Guru Subramanian Guru Murthy, Mehdi Hamadani, Laura C Michaelis, Karen-Sue Carlson, Lyndsey Runaas, Katelyn Gauger, Avinash G Desai, Mary M Chen, Kate L Li, Mojisola Rotibi, Umar Syed, Madhuri Vusirikala, Alexandra Harrington, Ehab L Atallah.
      Lintuzumab-Ac255 is a humanized anti-CD33 antibody linked to Actinium-225 delivering high-energy alpha-particles to leukemia cells, inciting double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Primary objectives were determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety. Using a 3 + 3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25-1.0 µCi/kg) 7 ( + 2) days after CLAG-M (days 1-6); 5 additional patients received the RP2D. Of evaluable patients, 86.7% had high-risk disease. The MTD and RP2D was 0.75 µCi/kg. Common grade 3/4 adverse events were febrile neutropenia (65.4%) and decreased white blood cells (50%). The composite complete remission (CRc) rates (CR/CRi) were 56.6% overall, 50% in patients with mutated TP53, and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity was achieved in 8 of 12 responders. Among all patients (n = 26), estimated 2-year OS was 23.1% (95% CI, 9.4-40.3) and estimated 1-year PFS was 30.8% (95% CI, 14.6-48.5). Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep and meaningful responses in high-risk R/R AML patients.
    DOI:  https://doi.org/10.1038/s41375-025-02528-3
  7. Am J Hematol. 2025 Mar;100 Suppl 2 38-49
    Maintenance Therapy in AML: What Is the Future Potential?
    Hannah Goulart, Andrew H Wei, Tapan M Kadia.
      Over the last decade, there have been significant advancements in the treatment for patients with acute myeloid leukemia (AML) including the addition of novel, targeted agents to intensive or nonintensive chemotherapy regimens. However, despite this, the majority of patients will still ultimately relapse and long-term survival remains poor. While the use of maintenance therapy has emerged as a potential strategy to maintain more durable remissions and improve overall survival, the optimal use of these therapies has not yet been clearly defined. In this review, we provide a comprehensive overview of the evolution of maintenance strategies in AML and present a commentary on the future of maintenance therapy, including the pressing, unmet needs in this field.
    Keywords:  AML; AML molecular diagnosis and therapy; chemotherapy; leukemia
    DOI:  https://doi.org/10.1002/ajh.27583
  8. Br J Haematol. 2025 Feb 21.
    Immune-deficient MISTRG mice support expansion of leukaemia-initiating cells in xenograft models of paediatric acute myeloid leukaemia.
    Patrick Connerty, Jinhan Xie, Fatima El-Najjar, Toby N Trahair, Nisitha Jayatilleke, Chelsea Mayoh, Richard B Lock.
      Acute myeloid leukaemia (AML) remains a deadly disease, largely due to the persistence of drug-resistant leukaemia-initiating cells (LICs) which promote relapse. Therefore, effective therapies must target LICs. Patient-derived xenografts (PDXs) are valuable for testing new therapies, though establishing AML PDX models is challenging. Two humanized mouse strains, MISTRG and NRGS, have been developed for this purpose. In this study, we show both are suitable strains for the development of AML PDXs; however, MISTRG-derived PDXs contain 10 times higher LIC frequencies than NRGS-derived PDXs. These differences have crucial implications for preclinical AML therapy testing and modelling relapse models of the disease.
    Keywords:  MISTRG; NRGS; acute myeloid Leukaemia; leukaemia‐initiating cells; patient‐derived xenograft
    DOI:  https://doi.org/10.1111/bjh.20029
  9. Blood. 2025 Feb 20. pii: blood.2024025337. [Epub ahead of print]
    Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease.
    Julie R Boiko, Kathleen S Ensbey, Olivia G Waltner, Isaac C Jenkins, Shruti S Bhise, Kelli Pa MacDonald, Bruce R Blazar, Anne Marcie Hall, Ted A Gooley, Simone A Minnie, Stephanie J Lee, Scott N Furlan, Geoffrey R Hill.
      Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutics agents targeting dysregulated cytokines including IL-17 and CSF-1 have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent FDA approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the US, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single cell sequencing-based approaches in our informative preclinical cGVHD models to "reverse engineer" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, non-intuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocytes within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 post-HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and non-responders to relevant therapeutics targeting these pathways.
    DOI:  https://doi.org/10.1182/blood.2024025337
  10. medRxiv. 2025 Jan 22. pii: 2025.01.21.25320683. [Epub ahead of print]
    Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98 -rearranged leukemia.
    Masayuki Umeda, Ryan Hiltenbrand, Nicole L Michmerhuizen, Juan M Barajas, Melvin E Thomas, Bright Arthur, Michael P Walsh, Guangchun Song, Jing Ma, Tamara Westover, Amit Kumar, Petri Pölönen, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore N Bertuccio, Martina Pigazzi, Shondra M Pruett-Miller, Stanley Pounds, Jeffrey Rubnitz, Hiroto Inaba, Kyriakos P Papadopoulos, Michael J Wick, Ilaria Iacobucci, Charles G Mullighan, Jeffery M Klco.
      Leukemias with NUP98 rearrangements exhibit heterogeneous phenotypes correlated to fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177 NUP98 -rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the same NUP98 fusions, such as NUP98::KDM5A acute megakaryocytic leukemia with RB1 loss or T-cell acute lymphoblastic leukemia with NOTCH1 mutations. CUT&RUN profiling reveals that NUP98 fusion oncoproteins directly regulate differentiation-related genes, with binding patterns also influenced by differentiation stage. Using in vitro models, we show RB1 loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereas WT1 frameshifts skew differentiation toward dormant lympho-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells. NUP98::KDM5A models with RB1 or WT1 alterations have different sensitivities to menin inhibition, suggesting cellular differentiation stage-specific resistant mechanism against menin inhibitors with clinical implications for NUP98 -rearranged leukemia.
    DOI:  https://doi.org/10.1101/2025.01.21.25320683
  11. Haematologica. 2025 Feb 20.
    A phase II trial of azacitidine with ipilimumab, nivolumab, or ipilimumab and nivolumab in previously untreated myelodysplastic syndrome.
    Ian M Bouligny, Guillermo Montalban-Bravo, Koji Sasaki, Naval Daver, Elias Jabbour, Yesid Alvarado, Courtney D DiNardo, Farhad Ravandi, Gautam Borthakur, Prithviraj Bose, Naveen Pemmaraju, Steven Kornblau, Tapan Kadia, Lucia Masarova, Koichi Takahashi, Michael Andreeff, Alexandre Bazinet, Hui Yang, Rashmi Kanagal-Shamanna, Chitra Hosing, Sherry Pierce, Meghan Meyer, Xuelin Huang, Guillermo Garcia-Manero.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286559
  12. Trends Cancer. 2025 Feb 14. pii: S2405-8033(25)00012-3. [Epub ahead of print]
    Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations.
    Ludovic Gabellier, Enzo Bosetta, Maël Heiblig, Jean-Emmanuel Sarry.
      Pathogenic variants of isocitrate dehydrogenase 1 and 2 (IDH1/2) genes are present in approximately 20% of acute myeloid leukemia (AML) cases, resulting in the oncometabolite R-2-hydroxyglutarate (R-2-HG). The accumulation of R-2-HG in leukemic cells and in their niche induces epigenetic modifications, profound rewiring of the cellular metabolism, and microenvironmental remodeling. These changes promote cellular differentiation bias, enhancing the survival and proliferation of leukemic cells, and thus playing a pivotal role in leukemogenesis and resistance to standard AML therapy. This review focuses on the different perspectives offered by studying metabolism and resistance to standard treatments in AML with IDH1 or IDH2 pathogenic variants, for the development of new biomarkers and therapeutic solutions.
    Keywords:  isocitrate dehydrogenase; leukemia; metabolism; resistance; therapy
    DOI:  https://doi.org/10.1016/j.trecan.2025.01.011
  13. Exp Hematol. 2025 Feb 12. pii: S0301-472X(25)00037-2. [Epub ahead of print] 104746
    Preconditioning intervention before allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia.
    Takayoshi Tachibana, Akihiko Izumi, Shota Arai, Takaaki Takeda, Natsuki Hirose, Yotaro Tamai, Shuku Sato, Chizuko Hashimoto, Katsumichi Fujimaki, Ryuji Ishii, Hirotaka Sakai, Etsuko Yamazaki, Yasuyuki Inoue, Masatsugu Tanaka, Hideaki Nakajima.
      The outcomes of patients with high-risk acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HCT) remain poor despite many attempts at developing therapeutic strategies. Preconditioning interventions (PCIs) have been applied to patients with high-risk AML to reduce the disease burden before starting the conditioning regimen. A single-center retrospective study was performed to evaluate the safety and efficacy of PCI in allograft patients with high-risk AML. Thirty-three patients with a median age of 57 (16-70) years were included to the entire cohort. Among various PCI regimens, venetoclax plus azacitidine was administered to 12 patients. The median drug withdrawal day was 0 days (range, 0-12) for low-intensity PCIs and 12 days (range, 8-14) for high-intensity PCIs. With no grade 3 nonhematological adverse events during PCIs, the median blast fraction in the bone marrow before and after PCIs decreased from 12.4% to 2.1% (p = 0.001). Excluding three patients with early complication-related deaths, all 30 patients achieved engraftment within a median of 30 days. The overall survival, cumulative incidence of relapse, and nonrelapse mortality (NRM) rates at 2 years were 67.1%, 23.9%, and 8.8%, respectively. The cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) at 100 days and chronic GVHD at 2 years were 32.4% and 23.5%, respectively. PCI may be safe and effective in promoting engraftment and reducing the risk of disease relapse without increasing the risk of NRM. Further clinical trials are warranted to establish appropriate PCI strategies.
    DOI:  https://doi.org/10.1016/j.exphem.2025.104746
  14. Proteomes. 2025 Feb 17. pii: 11. [Epub ahead of print]13(1):
    Proteomic Comparison of Acute Myeloid Leukemia Cells and Normal CD34+ Bone Marrow Cells: Studies of Leukemia Cell Differentiation and Regulation of Iron Metabolism/Ferroptosis.
    Frode Selheim, Elise Aasebø, Håkon Reikvam, Øystein Bruserud, Maria Hernandez-Valladares.
      Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy that can be cured only by intensive chemotherapy possibly combined with allogeneic stem cell transplantation. We compared the pretreatment proteomic profiles of AML cells derived from 50 patients at the time of first diagnosis with normal CD34+ bone marrow cells. A comparison based on all AML and CD34+ normal cell populations identified 121 differentially abundant proteins that showed at least 2-fold differences, and these proteins included several markers of neutrophil differentiation (e.g., TLR2, the integrins ITGM and ITGX, and downstream mediators including RHO GTPase, S100A8, S100A9, S100A22). However, the expression of these 121 proteins varied between patients, and a subset of 28 patients was characterized by increased long-term AML-free survival, signs of myeloid AML cell differentiation, and favorable genetic abnormalities. These two main patient subsets (28 with differentiation versus 22 with fewer signs of differentiation) also differed with regard to the phosphorylation of 16 differentially abundant proteins. Furthermore, we also classified our patients based on their expression of 16 proteins involved in the regulation of iron metabolism/ferroptosis and showing differential expression when comparing AML cells and normal CD34+ cells. Among the 22 patients with less favorable prognosis, we could then identify a genetically heterogeneous subset characterized by adverse prognosis (i.e., death from primary resistance/relapse) and an iron metabolism/ferroptosis protein profile showing similarities with normal CD34+ cells. We conclude that proteomic profiles differ between AML and normal CD34+ cells; especially, proteomic differences reflecting differentiation and regulation of iron metabolism/ferroptosis are associated with risk of relapse after intensive conventional therapy.
    Keywords:  Toll-like receptor; acute myeloid leukemia; cellular communication; differentiation; hematopoiesis; integrin; intracellular signaling; mass spectrometry; normal CD34+ bone marrow cells; patient heterogeneity; proteomics
    DOI:  https://doi.org/10.3390/proteomes13010011
  15. Blood Adv. 2025 Feb 19. pii: bloodadvances.2024014728. [Epub ahead of print]
    Improved Outcome and Therapeutic Directions in Pediatric Therapy-related AML: Recommendations by the AML-BFM Study Group.
    Stephanie Sendker, Markus Schneider, Evangelia Antoniou, Daniel Neumann, Nagmeh Niktoreh, Uta Dirksen, Nils Von Neuhoff, Ursula Creutzig, Dirk Reinhardt, Katharina Waack.
      Therapy-related acute myeloid leukemia (tAML) is one of the most feared therapy-emergent complications. This study aims to determine the clinical and pathological significance, to define therapeutic implications and poor prognosticators in pediatric tAML. We analyze a total of 119 pediatric patients (2 to 20 years), who were centrally diagnosed with tAML within the AML-BFM study group between 1993 and 2019. Compared with de-novo AML, tAML was associated with decreased white blood count and involvement of the central nervous system. Latency to tAML was inversely correlated with age at primary malignancy. Patients with tAML were more likely to have abnormal karyotypes, over-representing KMT2A-rearrangements, the unfavorable cytogenetics -7/del(7q), complex and monosomal karyotypes while core-binding AML were underrepresented. The occurrence of stratification-relevant molecular genetics was comparable with de-novo AML while CEBPAdm was absent in tAML. Survival rates in tAML improved from 10±6% in AML-BFM 93/98 to 50±10% in the registries 2012/2017, though, this is still worse compared to de-novo AML. Hematopoietic stem-cell transplantation (HSCT) in no evidence of leukemia (NEL, < 5% blasts) following two induction cycles greatly improved survival. Adverse cytogenetics, previous ionizing radiation (> 35 Gray), and latency ≤ 1 year were identified as the strongest poor prognosticators. Over the past 26 years, outcome and survival significantly improved in pediatric tAML. Our results suggest HSCT in NEL following two induction cycles as the most promising therapeutic approaches for achieving improved survival. Radiation, adverse cytogenetics, and latency ≤ 1 year should be considered as poor prognosticators in pediatric tAML.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014728
  16. Cell Death Dis. 2025 Feb 18. 16(1): 107
    CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia.
    Lisa Scheiblecker, Thorsten Klampfl, Eszter Doma, Sofie Nebenfuehr, Omar Torres-Quesada, Sophie Strich, Gerwin Heller, Daniela Werdenich, Waltraud Tschulenk, Markus Zojer, Florian Bellutti, Alessia Schirripa, Sabine Zöchbauer-Müller, Peter Valent, Ingrid Walter, Eduard Stefan, Veronika Sexl, Karoline Kollmann.
      Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. The cell cycle kinase CDK6 has recently been implicated in a wide range of hematopoietic malignancies. We here investigate the role of CDK6 in the regulation of cellular metabolism in BCR::ABL1+ leukemic cells. Our study, using gene expression data and ChIP-Seq analysis, highlights the contribution of CDK6 kinase activity in the regulation of oxidative phosphorylation. Our findings imply a competition for promoter interaction of CDK6 with the master regulator of mitochondrial respiration, NRF-1. In line, cells lacking kinase active CDK6 display altered mitochondria morphology with a defective electron transport chain. The enhanced cytoplasm/mitochondria ATP ratio paralleled by high pyruvate and lactate levels indicate a metabolic switch to glycolysis. Accordingly, combinatorial treatment of leukemic cells including imatinib resistant cells with the CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglucose (2-DG) enhanced apoptosis, while blocking cell proliferation in leukemic cells. These data may open a new therapeutic avenue for hematologic malignancies with high CDK6 expression by exploiting metabolic vulnerabilities unmasked by blocking CDK6 kinase activity that might even be able to overcome imatinib resistance.
    DOI:  https://doi.org/10.1038/s41419-025-07434-1
  17. Haematologica. 2025 Feb 20.
    Venetoclax in combination with hypomethylating agents in newly diagnosed and relapsed CBFβ::MYH11+ acute myeloid leukemia.
    Ziyu Feng, Xiaohui Hu, Weiyang Li, Ting Xu, Yang Xu, Shengli Xue, Huiying Qiu, Xiaowen Tang, Yue Han, Suning Chen, Aining Sun, Yanming Zhang, Depei Wu, Ying Wang.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286836
  18. Br J Haematol. 2025 Feb 19.
    Oral iptacopan for paroxysmal nocturnal haemoglobinuria-First real-world experience.
    Richard J Kelly, Austin G Kulasekararaj, Louise M Arnold, Catherine Barnfield, Isla Storey, Jessica Molyneux, Nora L Youngs, Joanna Large, Lindsay Mitchell, Sateesh K Nagumantry, Shreyans Gandhi, Roochi Trikha, Abraham Varghese, Talha Munir, Petra Muus, Morag Griffin.
      
    DOI:  https://doi.org/10.1111/bjh.20024
  19. bioRxiv. 2025 Jan 27. pii: 2025.01.24.634753. [Epub ahead of print]
    Single Cell Spatial Transcriptomics Reveals Immunotherapy-Driven Bone Marrow Niche Remodeling in AML.
    Gege Gui, Molly A Bingham, Julius R Herzog, Abigail Wong-Rolle, Laura W Dillon, Meghali Goswami, Eddie Martin, Jason Reeves, Sean Kim, Arya Bahrami, Hermann Degenhardt, George Zaki, Prajan Divakar, Edward C Schrom, Katherine Calvo, Christopher S Hourigan, Kasper Hansen, Chen Zhao.
      Given the successful graft-versus-leukemia cell treatment effect observed with allogeneic hematopoietic stem cell transplant for patients with refractory or relapsed acute myeloid leukemia, immunotherapies have also been investigated in the nontransplant setting. Here, we use a multi-omic approach to investigate spatiotemporal interactions in the bone marrow niche between leukemia cells and immune cells in patients with refractory or relapsed acute myeloid leukemia treated with a combination of the immune checkpoint inhibitor pembrolizumab and hypomethylating agent decitabine. We derived precise segmentation data by extensively training nuclear and membrane cell segmentation models, which enabled accurate transcript assignment and deep learning-feature-based image analysis. To overcome read-depth limitations, we integrated the single-cell RNA sequencing data with single-cell-resolution spatial transcriptomic data from the same sample. Quantifying cell-cell distances between cell edges rather than cell centroids allowed us to conduct a more accurate downstream analysis of the tumor microenvironment, revealing that multiple cell types of interest had global enrichment or local enrichment proximal to leukemia cells after pembrolizumab treatment, which could be associated with their clinical responses. Furthermore, ligand-receptor analysis indicated a potential increase in TWEAK signaling between leukemia cells and immune cells after pembrolizumab treatment.
    Highlights: Spatial transcriptomic analysis of R-AML bone marrow niches provides detailed information about intercellular interactions in the tumor microenvironment.Immunotherapy shifts the cell composition of the leukemia neighborhood.
    Graphical abstract:
    DOI:  https://doi.org/10.1101/2025.01.24.634753
  20. Am J Hematol. 2025 Mar;100 Suppl 2 16-22
    Frontline Therapy of AML in the Fit and Younger Population-Incorporating Molecularly Targeted Agents.
    Keith W Pratz, Harry P Erba.
      Backbone therapy for acute myeloid leukemia for younger adults has for 50 years been based on a combination of cytarabine and anthracycline. Over the past 10 years the addition of several targeted agents has been found to improve the outcomes of subsets of AML with particular molecular changes. In this review we will examine the data generated to date on the addition of agents targeting CD33, FLT3, IDH, and BCL2 to standard high intensity therapies. We will also review the potential for future studies evaluating the application of highly active lower intensity therapies developed in older adults to patients considered "fit for high intensity induction." Lastly, we review the data around the role of stem cell transplant in the modern targeted era.
    Keywords:  AML; AML‐molecular diagnosis and therapy; Acute myeloid leukemia; Induction chemotherapy;  Targeted therapy
    DOI:  https://doi.org/10.1002/ajh.27585
  21. Nature. 2025 Feb 19.
    Cooperative nutrient scavenging is an evolutionary advantage in cancer.
    Gizem Guzelsoy, Setiembre D Elorza, Manon Ros, Logan T Schachtner, Makiko Hayashi, Spencer Hobson-Gutierrez, Parker Rundstrom, Julia S Brunner, Ray Pillai, William E Walkowicz, Lydia W S Finley, Maxime Deforet, Thales Papagiannakopoulos, Carlos Carmona-Fontaine.
      The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources1,2. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood3,4. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point5,6. Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.
    DOI:  https://doi.org/10.1038/s41586-025-08588-w
  22. J Clin Invest. 2025 Feb 18. pii: e187778. [Epub ahead of print]
    Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome.
    Usua Oyarbide, Valentino Bezzerri, Morgan Staton, Christian Boni, Arish Shah, Marco Cipolli, Eliezer Calo, Seth J Corey.
      Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency, and bony abnormalities with an increased risk of myeloid neoplasia. Almost all cases of SDS result from biallelic mutations in SBDS. SBDS interacts with EFL1 to displace EIF6 from the 60S ribosomal subunit. Released EIF6 permits the assembly of ribosomal large and small subunits in the cytoplasm. Decreased EIF6 levels due to haploinsufficiency or missense mutations which lead to decreased protein expression may provide a somatic genetic rescue and anti-leukemic effects. We observed accumulation of EIF6 protein in sbds knockout (KO) zebrafish models, confirmed in patient-derived tissues, and correlated with changes in ribosome proteins and TP53 pathways. The mechanism of action for this adaptive response is unknown. To address this, we generated an eif6 zebrafish KO line which do not survive past 10 days post fertilization. We also created two mutants with low Eif6 expression, 5-25% of the wildtype levels, that can survive until adulthood. We bred them with sbds-null strains and analyzed their phenotype and biochemical properties. Low Eif6 levels reduced Tp53 pathway activation but did not rescue neutropenia in Sbds-deficient zebrafish. Further studies elucidating the interplay between SBDS, EIF6, TP53, and cellular stress responses offer promising insights into SDS pathogenesis, somatic genetic rescue, and therapeutic strategies.
    Keywords:  Bone marrow; Genetics; Hematology; Leukemias; Neutrophils; Oncology
    DOI:  https://doi.org/10.1172/JCI187778
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