bims-tremyl 2025-09-28 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–09–28
28 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Omacetaxine and venetoclax in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome with mutant RUNX1.
MECOM fusion partner and bone marrow blast percentage influence outcomes of patients with MECOM rearranged acute myeloid leukaemia.
Ziftomenib in Relapsed or Refractory NPM1-Mutated AML.
SRSF2 mutations in CCUS, MDS and AML: a cross-entity study.
Determining telomere content and genomics of myeloid neoplasia by whole-genome sequencing.
CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias.
Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.
Fusion Gene Depletion Eliminates Stemness and Induces Bidirectional Differentiation of Acute Myeloid Leukemia.
Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine/cytarabine-based salvage regimens against acute myeloid leukaemia.
Allogeneic haematopoietic cell transplantation in advanced systemic mastocytosis in new era: A CIBMTR study.
Androgen receptor signaling as a new target for intervention in acute myeloid leukemia.
Remission status prior allogeneic stem cell transplantation in AML/MDS patients harboring single-hit or multi-hit p53 mutations does not impact outcome.
FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia.
LncRNA AC021683.2 promotes chemotherapy resistance in acute myeloid leukemia.
Clonal tracing of blood stem cells across mouse and human lifespans.
Myeloproliferative Neoplasms-Unclassifiable (MPN-U): A Carefully Curated Series of 30 Mayo Clinic Patients.
Bicistronic CAR T-cells Against CD70 & Active Integrin β2 Overcome Antigen Heterogeneity and Preserve Safety in Acute Myeloid Leukemia.
Rapid epigenomic classification of acute leukemia.
Epigenetic dysregulation and therapeutic targeting of RET receptor tyrosine kinase in high-risk KMT2A-rearranged acute myeloid leukaemia.
Rapid and durable recovery of immune effector cells in myelofibrosis patients treated with momelotinib.
Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome.
Building a transparent and functional lab culture: Guidelines for creating a Laboratory Handbook for principal investigators.
siRNA Mediated Genetic Perturbation of Primary Human Leukemia Stem and Progenitor Cells.
Three-dimensional Genome Reorganization in Hematopoietic Stem Cells.
EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers.
Detection of minimal residual disease in circulating cell-free DNA in acute myeloid leukemia.
Loss of life expectancy in patients with myeloproliferative neoplasms in Sweden.
Reprogramming neuroblastoma by diet-enhanced polyamine depletion.

Blood Neoplasia. 2025 Nov;2(4): 100145

Omacetaxine and venetoclax in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome with mutant RUNX1.

Courtney D DiNardo, Wei-Ying Jen, Guillermo Montalban-Bravo, Xuemei Wang, Sanam Loghavi, Sravanthi Lavu, Nicholas J Short, Kelly Chien, Ghayas C Issa, Naveen Pemmaraju, Musa Yilmaz, Michael Andreeff, Gautam Borthakur, Tapan M Kadia, Naval G Daver, Guillermo Garcia-Manero, Christopher P Mill, Xiaoping Su, Warren Fiskus, Kapil N Bhalla.

Mutations in RUNX1 (RUNX1 mut) occur in 10% to 20% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and are associated with poor outcomes to standard therapy. Omacetaxine mepesuccinate (OM), a semisynthetic analog of homoharringtonine, has been shown to be lethal to RUNX1 mut AML cells in vitro through reduction of MCL1 and BCL-XL, and synergizes with venetoclax (VEN) in RUNX1 mut AML models. We investigated the safety and efficacy of OM + VEN in relapsed/refractory RUNX1 mut MDS/AML in a Bayesian Optimal Interval design. VEN 400 mg daily from days 1 to 14 and OM 1.25 mg/m2 twice daily from days 2 to 4 was selected as the recommended phase 2 dose. Twenty-four patients were treated, 22 with AML and 2 with MDS with excess blasts. There were no dose-limiting toxicities or episodes of tumor lysis syndrome. The most common grade ≥3 toxicity was infection. There were no responses in our heavily pretreated cohort of patients with AML. Both patients with MDS achieved composite complete remission and transitioned to allogeneic stem cell transplant. Treatment-induced downregulation in gene expression in the β-catenin and hedgehog signaling pathway genes were identified in peripheral blood mononuclear cells from patients who responded. As compared to nonresponders, samples from responders also exhibited reduced antiapoptotic and increased proapoptotic protein expression. OM can synergize with VEN to promote loss of viability of myeloid cells. Clinical responses were seen exclusively in patients with MDS, which suggests that dose optimization or combination with cytoreductive agents may be necessary for eliciting clinical activity in AML. This trial was registered at www.ClinicalTrials.gov as #NCT04874194.

DOI: https://doi.org/10.1016/j.bneo.2025.100145
Br J Haematol. 2025 Sep 22.

MECOM fusion partner and bone marrow blast percentage influence outcomes of patients with MECOM rearranged acute myeloid leukaemia.

Wei-Ying Jen, Guilin Tang, Eitan Kugler, Jennifer Croden, Koji Sasaki, Alexandre Bazinet, Alex Bataller, Guillermo Montalban-Bravo, Gautam Borthakur, Gokce A Toruner, Sanam Loghavi, Nicholas J Short, Ghayas C Issa, Ian M Bouligny, Sherry Pierce, Uday Popat, Naveen Pemmaraju, Elias Jabbour, Guillermo Garcia-Manero, Kapil Bhalla, Farhad Ravandi, Naval G Daver, Courtney D DiNardo, Hagop M Kantarjian, Tapan M Kadia.

  MECOM rearrangements (MECOM-r) are acute myeloid leukaemia (AML)-defining, regardless of blast percentage or MECOM fusion partner. We sought to investigate if blast percentage or MECOM-r partner was associated with overall survival (OS). We included 152 adult patients with newly diagnosed MECOM-r and classified blast percentage into <20% or ≥20% and MECOM-r partner into classic (GATA2::MECOM) or variant (others). Thirty-one per cent had <20% blasts, with 69% having ≥20%; 57% had classic and 43% variant MECOM-r. Treatment was with intensive chemotherapy (IC) in 41% and low-intensity therapy (LIT) in 59%. Composite complete remission rates were similar between IC (50%) and LIT (48%, p = 0.99). The median OS was 17 months (95% confidence interval [CI], 12-not estimable [NE]) for <20% blasts, compared with 9 months (95% CI, 6-10) for ≥20% blasts (p < 0.01). On multivariate analysis, ≥20% blasts were associated with worse OS (hazard ratio [HR] 1.9, [95% CI, 1.2-3.2], p < 0.01), independent of age, MECOM-r partner, additional cytogenetic abnormalities, treatment intensity, addition of venetoclax and stem cell transplant (SCT). HR for IC was 2.0 (95% CI, 1.1-3.7, p = 0.03). In <20% blasts, variant MECOM-r was independently associated with a reduced hazard of death (HR 0.2 [95% CI, 0.1-0.8], p < 0.01). MECOM-r AML is a heterogenous entity; consideration should be given to LIT approaches.

Keywords:  AML; atypical MECOM; inv(3)(q21.3q26.2); t(3;3)(q21.3;q26.2); variant MECOM

DOI:  https://doi.org/10.1111/bjh.70171
J Clin Oncol. 2025 Sep 25. JCO2501694

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML.

KOMET-001

PURPOSE: Ziftomenib-a potent, highly selective, oral menin inhibitor-was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1-mutated (NPM1-m) and KMT2A-rearranged AML in the KOMET-001 phase I trial.
METHODS: In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1-m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh).
RESULTS: From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events.
CONCLUSION: Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1-m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

DOI: https://doi.org/10.1200/JCO-25-01694
Blood Neoplasia. 2025 Nov;2(4): 100144

SRSF2 mutations in CCUS, MDS and AML: a cross-entity study.

Sandra Huber, Sarah Ochmann, Stephan Hutter, Veronika Ecker, Manja Meggendorfer, Gregor Hoermann, Torsten Haferlach, Claudia Haferlach, Isolde Summerer.

DOI: https://doi.org/10.1016/j.bneo.2025.100144
Blood. 2025 Sep 22. pii: blood.2025028644. [Epub ahead of print]

Determining telomere content and genomics of myeloid neoplasia by whole-genome sequencing.

Luca Guarnera, Adam Wahida, Carmelo Gurnari, Stephan Hutter, Sabine A Stainczyk, Nakisha Williams, Arda Durmaz, Yasuo Kubota, Carlos Bravo-Perez, Naomi Kawashima, Mark David Orland, Simona Pagliuca, Yimin Huang, Thomas LaFramboise, Valeria Visconte, Wencke Walter, Manja Meggendorfer, Wolfgang Kern, Frank Westermann, Lars Feuerbach, Torsten Haferlach, Jaroslaw P Maciejewski.

Telomere length shortening has been associated with genomic instability and acquisition of molecular lesions, but these processes have not been systematically studied across large cohorts of myeloid neoplasia (MN). As proof of concept for a novel, cross-validated WGS-based method of telomere content (TC) determination combined with mutations, transcriptomics, and functional assays, we studied TC in correlation with specific molecular features of a large cohort (n=1804) of MN patients including acute myeloid leukemia (AML) and myelodysplastic syndrome. When compared to healthy subjects and patients with non-clonal diseases such as persistent polyclonal B cell lymphocytosis, both MN and non-malignant controls with clonal disease, such as paroxysmal nocturnal hemoglobinuria and aplastic anemia, exhibited decreased TC. Furthermore, we show that TC is lowered in adult MN abrogating correlation with age with considerable TC diversification among certain morphologic and molecular subtypes. For instance, AML harbored the lowest TC. Furthermore, MN originating from a more mature cell of origin (e.g., APL), and those characterized by hyperproliferative driver mutations (e.g., RAS pathway genes) had lower TC, possibly indicating a loss of telomere maintenance capacity. In contrast, MN subtypes arising in a context of profound genetic alterations, such as TP53 mutations and complex karyotype, exhibited a relatively higher/preserved TC compared to other mutations. This phenomenon did not involve alternative lengthening processes but was rather consistent with an increased TC due to preserved activity of the telomerase complex. Our results describe a common and genotype-specific telomeric make-up of a large cohort of patients with MN providing a molecular benchmark for future therapeutic targeting of the telomere machinery.

DOI: https://doi.org/10.1182/blood.2025028644
Blood. 2025 Sep 24. pii: blood.2025028954. [Epub ahead of print]

CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias.

Travis Fleming, Mateusz Antoszewski, Sander Lambo, Michael Gundry, Riccardo Piussi, Lara Wahlster, Sanjana B Shah, Fiona Reed, Kevin Dong, Joao A Paulo, Steven Gygi, Claudia A Mimoso, Seth Goldman, Karen Adelman, Jennifer A Perry, Yana Pikman, Kimberly Stegmaier, Maria N Barrachina, Kellie R Machlus, Volker Hovestadt, Andrea Arruda, Mark D Minden, Richard A Voit, Vijay G Sankaran.

Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem-cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem-cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem-cell-like states by directly repressing pro-differentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. These findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.

DOI: https://doi.org/10.1182/blood.2025028954
Mol Oncol. 2025 Sep 21.

Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.

Joseph Saad, Rhiannon Newman, Elmira Khabusheva, Sofia Aakko, Eric Durand, Mahesh Tambe, Heikki Kuusanmäki, Alun Parsons, Juho J Miettinen, Komal Kumar Javarappa, Ezgi June Olgac, Nemo Ikonen, Mika Kontro, Kimmo Porkka, Heiko Maacke, Janghee Woo, Ensar Halilovic, Caroline A Heckman.

  Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), clinical progress has been hindered by limited knowledge of target patient subgroups. To stratify patients for MCL-1 inhibitor treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and analyzed their molecular profiles. We observed that MIK665-sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti-apoptotic protein BCL-XL. Moreover, ABCB1 expression had good predictive performance in identifying resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. The combination of MIK665 with each of elacridar, tariquidar, or venetoclax effectively eliminated AML blasts compared to the agents alone, while the combination with A1331852 showed limited efficacy for this patient subgroup. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition.

Keywords:  MCL‐1 inhibition; acute myeloid leukemia; apoptosis; combination therapies; multidrug resistance‐associated proteins; prognostic biomarkers

DOI:  https://doi.org/10.1002/1878-0261.70130
Blood. 2025 Sep 24. pii: blood.2025028988. [Epub ahead of print]

Fusion Gene Depletion Eliminates Stemness and Induces Bidirectional Differentiation of Acute Myeloid Leukemia.

Polina K Derevyanko, Laura E Swart, L Daniel Mata Casimiro, Anita van Oort, Manisha Du Plessis, Luca van den Brink, Minoo Ashtiani, C Michel Zwaan, Anja Krippner-Heidenreich, Constanze Bonifer, Ray Michel Schiffelers, Josef Josef Vormoor, Sophie Kellaway, Olaf Heidenreich.

Chromosomal rearrangements that generate novel fusion genes are a hallmark of acute myeloid leukemia (AML). Depletion experiments in cell line models have suggested that their continued expression is required for maintaining their leukemic phenotype and that fusion genes therefore represent ideal cancer-specific therapeutic targets. However, to which extent this result holds true for the different stages of hematopoietic development in primary cells and whether therapeutic agents can be efficiently delivered to those cells is still unclear. In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using siRNA-loaded lipid nanoparticles induces substantial changes in chromatin accessibility, thereby redirecting the leukemia-associated transcriptional network towards a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity. These findings underscore the essential role of RUNX1::RUNX1T1 in sustaining AML and highlight the therapeutic potential of targeting fusion gene expression in primary AML cells.

DOI: https://doi.org/10.1182/blood.2025028988
Br J Haematol. 2025 Sep 27.

Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine/cytarabine-based salvage regimens against acute myeloid leukaemia.

Ingrid Lilienthal, Sijia Tao, Christer Nilsson, Elory Leonard, Runqing Zhang, Agnes L Sorteberg, Louisa Fredrikson, Ioanna Xagoraris, Shahrzad Shirazi Fard, Nikolaos Tsesmetzis, Vasilios Zachariadis, Huan Cai, Lakshmi Sandhow, Anette Langebäck, Anna Bohlin, Katja Pokrovskaja Tamm, Sofia Bengtzén, Raymond F Schinazi, Sören Lehmann, Baek Kim, Georgios Z Rassidakis, Hong Qian, Martin Jädersten, Nikolas Herold.

  Despite intensive treatment, patients with relapsed or refractory acute myeloid leukaemia (AML) have a dismal prognosis. A cornerstone therapy for relapsed/refractory AML is a combination of fludarabine (F-ara-A) and cytarabine (ara-C), so-called FLA. As the enzyme SAMHD1 mediates resistance to both ara-C and F-ara-A, we investigated whether SAMHD1 inhibition via hydroxyurea (hydroxycarbamide; HU) could improve FLA efficacy. Here, we show that HU synergistically enhanced ara-C-, F-ara-A- and FLA-induced cytotoxicity in an SAMHD1-dependent manner in AML cell lines, primary AML cells and an immunocompetent AML mouse model. Mechanistically, HU significantly increased the active metabolite triphosphates of ara-C and F-ara-A in FLA combinations. Furthermore, leukaemic SAMHD1 protein expression negatively correlated with overall survival in a cohort of FLA-treated refractory AML patients. Our findings suggest that the addition of HU improves the efficacy of FLA-based regimens and warrant clinical trials to test the safety and efficacy of this combination in patients with relapsed/refractory AML.

Keywords:  AML; SAMHD1; relapse/refractory

DOI:  https://doi.org/10.1111/bjh.70180
Br J Haematol. 2025 Sep 22.

Allogeneic haematopoietic cell transplantation in advanced systemic mastocytosis in new era: A CIBMTR study.

Celalettin Ustun, Mei-Jie Zhang, Andrew Peterson, Alexander Baek, Mounzer Agha, Hassan Alkhateeb, Saurabh Chhabra, Alex Coltoff, Marcos de Lima, Arpita Gandhi, Vincent Ho, Adetola Kassim, Adam Lin, Lohith Gowda, Gautam Borthakur, Daniel J DeAngelo, Joseph McGuirk, Felix Mensah, Kalyan V Nadiminti, Taiga Nishihori, Jeremy Pantin, Andrew Trunk, Joseph Uberti, Guido Marcucci, Jason Gotlib, Cem Akin, Mehdi Hamadani, Vinod Pullarkat, Peter Valent, Michael Grunwald, Mark Juckett, Betul Oran, Wael Saber, Linda J Burns.

  We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty-seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM-AHN, 70%), received peripheral blood grafts (89%) and non-myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post-transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre-alloHCT to 1.5% (range 0-8) at 1 year post-alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3-400 ng/mL) pre-alloHCT to 18 ng/mL (range 0-481 ng/mL) at 1 year post-alloHCT. At 1 year, progression-free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%-77%) and 74% (95% CI, 56%-89%) respectively. In the subset of patients with SM-AHN, 1-year PFS and OS were 74% (52%-91%) and 79% (95% CI, 58%-94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM (n = 27) was 4% (95% CI, 0-14) at 100 days and 15% (95% CI, 4-31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1-28) at 100 days and 21% (95% CI, 6-42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre- and post- alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.

Keywords:  allogeneic; bone marrow transplantation; mast cells; systemic mastocytosis; tryptase

DOI:  https://doi.org/10.1111/bjh.70154
Blood Adv. 2025 Sep 24. pii: bloodadvances.2024012639. [Epub ahead of print]

Androgen receptor signaling as a new target for intervention in acute myeloid leukemia.

Fenghua Qian, Deborpita Sarkar, Brooke E Arner, Vanessa M Peduzzi, Yuting Bai, Baiye Ruan, Bei Jia, Hong Zheng, Robert F Paulson, K Sandeep Prabhu.

In addition to their role in development, sex hormones and their cognate receptors play an important role in various malignancies. Using a murine model of human MLL-AF9 induced acute myeloid leukemia (AML), we discovered that high Androgen receptor (AR) expressing leukemia initiating cells (LICs) when transferred into either male or female recipients resulted in more severe disease than low AR-expressing LICs. AR expression was significantly increased in female LICs compared to male LICs. This difference was confined to the LICs and not present in normal bone marrow cells. AML cells from both sexes relied on AR signaling via different mechanisms-females had high AR with low ligand, males, low AR with high ligand. AR expression was linked to EPHA7-associated PI3K/AKT/MTOR and SRC/HIF-1α pathways. Use of the two US FDA approved drugs for prostate cancer, ARN509, an AR antagonist and finasteride, which inhibits the pathway that produces dihydrotestosterone, resulted in significant remission with increased survival of AML mice. ARN509 and finasteride also showed pro-apoptotic effect in patient-derived AML cells and in a humanized AML model in NSG mice. These data support a drug repurpose effort to use anti-androgen therapy to improve the efficacy of AML treatments.

DOI: https://doi.org/10.1182/bloodadvances.2024012639
Transplant Cell Ther. 2025 Sep 23. pii: S2666-6367(25)01463-0. [Epub ahead of print]

Remission status prior allogeneic stem cell transplantation in AML/MDS patients harboring single-hit or multi-hit p53 mutations does not impact outcome.

Normann Steiner, Evgeny Klyuchnikov, Anita Badbaran, Radwan Massoud, Nico Gagelmann, Ina Rudolph, Silke Heidenreich, Dominik Wolf, Gaby Zeck, Catherina Lueck, Francis Ayuketang Ayuk, Nicolaus Kröger.

   BACKGROUND: Patients with TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent a heterogeneous group and have a poor prognosis even after allogeneic stem cell transplantation (allo-SCT).
OBJECTIVE: This study examines the post-transplant outcomes of patients based on their pre-transplant TP53 mutational status to assess the impact of multi-hit and single-hit mutations.
STUDY DESIGN: A retrospective analysis was conducted on 81 adult patients with MDS/AML (30 with single-hit and 51 with multi-hit mutations) who underwent allo-SCT at the University Medical Center Hamburg between 2014 and 2024. The pre-transplant remission status was evaluated through cytomorphological, next-generation sequencing (NGS), and cytogenetic methodologies.
RESULTS: With a median age of 63 years (range from 18 to 78 years), 42 male patients were included in the study. Most patients had reduced intensity conditioning (62%), received allografts from unrelated donors (75%), and were categorized as non-CR (60%). The three-year overall survival (OS) and leukemia-free survival (LFS) rates were 25% and 23%, for patients with AML, and 43% and 30% for patients with MDS (p=0.20 and p=0.29, respectively). The three-year OS (34% vs 28% vs 42%, p=0.52) and LFS (32% vs 26% vs 26%, p=0.69) rates were comparable between patients in CR, those in non-CR and untreated at allo-SCT, respectively. The three-year OS rate for patients with a single-hit TP53 mutation was 35%, compared to 27% for patients with a multi-hit mutation (p=0.15). The three-year LFS rate for the single-hit cohort was 26%, compared to 18% for the multi-hit cohort (p=0.047). Patients treated with fludarabine and treosulfan showed the highest three-year OS (58%) and LFS (46%) rate compared to patients treated with other regimens (p=0.051 and p=0.025). The cumulative incidence of relapse (CIR) at three years was comparable between the multi- and single-hit cohorts (50% vs 56%, p=0.70). The patients with multi-hit status experienced post-transplant relapses earlier (median: 80 days (8-1107) vs 128 days (78-794), p=0.037). The cumulative incidence of non-relapse mortality at three years was 16% in the single-hit cohort and 29% in the multi-hit cohort (p=0.15). The majority of patients from the multi-hit cohort received more than two chemotherapy cycles before allo-SCT, in comparison to the single-hit cohort (p=0.14).
CONCLUSION: The multi-hit TP53 mutation was found to be significantly associated with a reduced LFS rate in MDS/AML patients, in comparison to those with a single-hit TP53 mutation. Patients with a single or multi-hit TP53 may achieve a long-term survival rate of approximately 30%, and should be considered as transplant candidates, even in the absence of complete remission.

Keywords:  acute myeloid leukaemia; allogeneic stem cell transplantation; graft-versus-host disease; multi-hit TP53 mutation; myelodysplastic syndromes; single-hit TP53 mutation

DOI:  https://doi.org/10.1016/j.jtct.2025.09.036
Cell Rep Med. 2025 Sep 19. pii: S2666-3791(25)00438-0. [Epub ahead of print] 102365

FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia.

Dengyang Zhang, Yao Guo, Zhiyong Peng, Yan Xiao, Zhiguang Chang, Liuting Yu, Yuming Zhao, Qi Zhang, Lingling Ma, Shuping Li, Chi-Kong Li, Kam Tong Leung, Zhizhuang Joe Zhao, Chun Chen, Yun Chen.

  Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor prognosis due to relapse and chemotherapy resistance. FLT3 mutations promote AML and predict adverse outcomes. As most AML cells express FLT3, it represents a promising therapeutic target. In this study, we develop FL-Fc-DM1, a FLT3-targeted conjugate linking FLT3 ligand-Fc to DM1. FL-Fc-DM1 demonstrates potent anti-leukemic activity in vitro, ex vivo, and in both cell line- and patient-derived xenograft models. Notably, it effectively targets cytarabine-resistant AML cells by promoting cell cycle entry and inducing apoptosis. FL-Fc-DM1 also significantly reduces functional leukemia stem cell frequency, as demonstrated by limiting dilution transplantation assays. The therapeutic efficacy can be further strengthened by BH3 mimetics. Importantly, toxicity assessments in a humanized mouse model show limited impact on normal human hematopoiesis at therapeutic doses. Our findings suggest that FL-Fc-DM1 is a promising candidate for AML treatment, even for cell cycle-arrested or slow-cycling chemo-resistant AML cells.

Keywords:  AML; DM1; FLT3; FLT3L; cell cycle; chemotherapy resistance; ligand-drug conjugate

DOI:  https://doi.org/10.1016/j.xcrm.2025.102365
iScience. 2025 Sep 19. 28(9): 113439

LncRNA AC021683.2 promotes chemotherapy resistance in acute myeloid leukemia.

Lan Li, Xue-Ni An, Yong-Tong Ruan, Xin Liang, Jing-Lan Hao, Guang-Xun Gao, Jun-Fang Bi, Yan-Rong Gao, Xiao Lu, Hai-Long Tang, Ping Gao, Xiao-Ming Dong.

  Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitors with poor clinical outcomes. Though many patients respond well to induction chemotherapy, relapse occurs. The mechanisms underlying AML chemoresistance remain unclear. In our study, we performed whole transcriptome sequencing (WTS) on diagnosed AML samples sensitive or resistant to IA (idarubicin and cytarabine) induction treatment. We observed that lncRNA AC021683.2 is upregulated in IA-resistant patients and associated with poor prognosis. AC021683.2 depletion increased the chemosensitivity of AML cells to Ara-C both in vitro and in vivo by accelerating BCLAF1 ubiquitination and degradation, and AC021683.2 depletion enhanced sensitivity partially by depending on BCLAF1. Both AC021683.2 and BCLAF1 positively correlated with RAD50, which mediated their roles in Ara-C-resistant AML cells. These findings demonstrated that the lncRNA AC021683.2 enhances the resistance of AML/Ara-C-resistant cells to Ara-C in vitro and in vivo, offering a potential target for treating Ara-C-resistant AML.

Keywords:  Biochemistry; Cancer; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2025.113439
Blood. 2025 Sep 22. pii: blood.2024028195. [Epub ahead of print]

Clonal tracing of blood stem cells across mouse and human lifespans.

Alejo E Rodriguez-Fraticelli.

For over sixty years, blood researchers have been counting clones with every tool at their disposal. Inspired by phage and fly geneticists, Till and McCulloch irradiated mice to induce chromosomal aberrations. Using this labeling strategy, they demonstrated that different types of blood cells shared the same mutation in every spleen colony, thereby proving the existence of hematopoietic stem cells. Since their breakthrough, technological advances have enabled researchers to quantify hematopoiesis at single-cell resolution in increasingly complex samples across both mice and humans. With these modern sophisticated lineage tracing methods, our foundational understanding of the blood system is being reshaped. For instance, we now interpret hematopoietic architecture as arising from stem and progenitor cells of diverse developmental origins, each with distinct fate biases encoded by unique regulatory states. Interacting with this regulatory layer, genetic mutations and epimutations arise, expanding clonally and becoming pervasive with age. Together, clonal heterogeneity and age-driven clonal selection may underlie the perplexing diversity of therapy responses in cancer and beyond. As these paradigm-shifting insights gain traction, clonal tracing is being adopted across dozens of biological and clinical studies. Here, we review the modern toolbox of clonal tracking technologies, with a focus on next-generation sequencing-based approaches, and provide a practical guide for matching specific research questions with optimal experimental strategies.

DOI: https://doi.org/10.1182/blood.2024028195
Am J Hematol. 2025 Sep 23.

Myeloproliferative Neoplasms-Unclassifiable (MPN-U): A Carefully Curated Series of 30 Mayo Clinic Patients.

Rania M Abdelaziz, Priyansh Faldu, Saubia Fathima, Cinthya J Zepeda Mendoza, Animesh Pardanani, Rong He, Attilio Orazi, Kaaren K Reichard, Naseema Gangat, Ayalew Tefferi.



Keywords:   ICC ; WHO ; bone marrow; prognosis; survival

DOI:  https://doi.org/10.1002/ajh.70085
bioRxiv. 2025 Sep 21. pii: 2025.09.21.677627. [Epub ahead of print]

Bicistronic CAR T-cells Against CD70 & Active Integrin β2 Overcome Antigen Heterogeneity and Preserve Safety in Acute Myeloid Leukemia.

Amrik S Kang, Haley Johnson, Nicole Lei, Jeremiah Wong, Nabeel Razi, Adila Izgutdina, Corynn Kasap, Nikhil Chilakapati, Jose Rivera, Paul Phojanakong, Juan Antonio Camara Serrano, Fernando Salangsang, Veronica Steri, Aaron C Logan, Justin Eyquem, Benjamin J Huang, Arun P Wiita.

The surface antigen landscape of acute myeloid leukemia (AML) displays significant heterogeneity and overlap with healthy hematopoietic cells. This imparts a substantial hurdle to the development of AML-targeting chimeric antigen receptor (CAR) T-cells that can avoid on-target, off-tumor toxicity. Here, we develop a dual-antigen targeting CAR-T against CD70 and the active conformation of integrin β2 (aITGB2), each previously reported as promising AML targets due to minimal off-tumor expression. We show an OR-gated approach for these antigens significantly increases the proportion of AML blasts that can be targeted, in part using a novel ex vivo co-culture method to restore surface protein homeostasis following a freeze-thaw cycle. We test dual-targeting CAR-T constructs with different combinations of costimulatory domains, identifying constructs with superior anti-tumor cytotoxicity in vitro against AML cell line and patient derived xenograft models. We further show significantly improved in vivo tumor clearance and survival for a dual targeting CAR in murine models of AML tumor heterogeneity. Finally, we show that this dual-targeting CAR does not increase off-tumor toxicity, especially against hematopoietic stem and progenitor cells. Together, these findings demonstrate a promising clinically-translatable approach for the treatment of AML without the notable toxicity liabilities associated with other leading CAR-T targets for this disease.

DOI: https://doi.org/10.1101/2025.09.21.677627
Nat Genet. 2025 Sep 22.

Rapid epigenomic classification of acute leukemia.

Til L Steinicke, Salvatore Benfatto, Maria R Capilla-Guerra, Andre B Monteleone, Jonathan H Young, Subha Shankar, Phillip D Michaels, Harrison K Tsai, Jonathan D Good, Antonia Kreso, Peter van Galen, Christoph Schliemann, Evan C Chen, Gabriel K Griffin, Volker Hovestadt.

Acute leukemia requires precise molecular classification and urgent treatment. However, standard-of-care diagnostic tests are time-intensive and do not capture the full spectrum of acute leukemia heterogeneity. Here, we developed a framework to classify acute leukemia using genome-wide DNA methylation profiling. We first assembled a comprehensive reference cohort (n = 2,540 samples) and defined 38 methylation classes. Methylation-based classification matched standard-pathology lineage classification in most cases and revealed heterogeneity in addition to that captured by genetic categories. Using this reference, we developed a neural network (MARLIN; methylation- and AI-guided rapid leukemia subtype inference) for acute leukemia classification from sparse DNA methylation profiles. In retrospective cohorts profiled by nanopore sequencing, high-confidence predictions were concordant with conventional diagnoses in 25 out of 26 cases. Real-time MARLIN classification in patients with suspected acute leukemia provided accurate predictions in five out of five cases, which were typically generated within 2 h of sample receipt. In summary, we present a framework for rapid acute leukemia classification that complements and enhances standard-of-care diagnostics.

DOI: https://doi.org/10.1038/s41588-025-02321-z
Br J Haematol. 2025 Sep 21.

Epigenetic dysregulation and therapeutic targeting of RET receptor tyrosine kinase in high-risk KMT2A-rearranged acute myeloid leukaemia.

Arundhati Chavan, Brendan Frett, Daniel T Armstrong, Baku Acharya, Pamela Lockyer, Marjan Boerma, Samrat Roy Choudhury.



Keywords:  CDK8‐MED12; KMT2A‐rearranged leukemia; RET‐receptor tyrosine kinase

DOI:  https://doi.org/10.1111/bjh.70183
Haematologica. 2025 Sep 25.

Rapid and durable recovery of immune effector cells in myelofibrosis patients treated with momelotinib.

Jasmine Makker, Kyaw Htin Thaw, Amna Sheikh, Llywelyn Cadman-Davies, Andrea Duminuco, Elena Torre, Margherita Panetta, Conor Stanley, Hugues De Lavallade, Natalia Curto-Garcia, Priya Sriskandarajah, Jennifer O'Sullivan, Deepti H Radia, Claire Woodley, Benissa Narciso, Susan Asirvatham, Bethan Psaila, Shahram Kordasti, Claire Harrison, Patrick Harrington.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.288515
bioRxiv. 2025 Sep 17. pii: 2025.09.15.676332. [Epub ahead of print]

Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome.

Varun S Sudunagunta, Edna M Stewart, Yi Chen, Hongxia Yan, Sebastian Fernando, Viviana Scoca, Jane J Xu, Narla Mohandas, Aaron D Viny.

The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. While mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 co-regulates divergent cell fates remains only partially characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome and Down Syndrome associated acute megakaryoblastic leukemia, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Hence, we hypothesized that chromatin accessibility facilitates lineage specificity of GATA1, thereby permitting efficient cellular differentiation. To understand the connection between chromatin accessibility and GATA1, we performed comprehensive studies of erythropoiesis in Stag2 Δ mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid maturation, increased number of MkPs, and increased megakaryocytes. RNA- and ATAC-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Gata1 occupancy was lost at erythroid targets, while occupancy increased at megakaryocyte targets. Functionally, we observed that Stag2-deficient EryPs have diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays. Human models and primary MDS patients recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study advances the understanding of the interplay between TF function and chromatin accessibility. Moreover, these data suggest a novel conceptual paradigm of dyserythropoiesis in MDS.
Key Points: xxxxx.

DOI: https://doi.org/10.1101/2025.09.15.676332
Exp Hematol. 2025 Sep 19. pii: S0301-472X(25)00554-5. [Epub ahead of print] 105265

Building a transparent and functional lab culture: Guidelines for creating a Laboratory Handbook for principal investigators.

Charles E de Bock, Katherine S Bridge, Nick van Gastel, Hélène F E Gleitz, Lev Kats, Katherine Y King, Kellie R Machlus, Bethan Psaila, Vanessa Scanlon, George P Souroullas, Konstantinos D Kokkaliaris.

DOI: https://doi.org/10.1016/j.exphem.2025.105265
bioRxiv. 2025 Sep 20. pii: 2025.09.17.676969. [Epub ahead of print]

siRNA Mediated Genetic Perturbation of Primary Human Leukemia Stem and Progenitor Cells.

Anagha Inguva, Hunter Tolison, Jeremy Rahkola, Craig T Jordan, Courtney Jones, Maria Amaya.

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are aggressive hematologic malignancies with poor outcomes. Leukemia stem and progenitor cells (LSPCs) are a subset of cells within the bulk tumor thought to be responsible for initiating disease and causing relapse. LSPCs evade chemotherapy partially due to their quiescent state. Therefore, studying this cell subpopulation is critical to identify new disease targets that can better the outcomes of AML/MDS patients. The use of RNAi and genetic approaches is technically challenging in primary leukemia cells and particularly LSPCs. Overcoming this technical hurdle could greatly expand the breath of pre-clinical and mechanistic examination of LSPCs. In this study, we describe a methodology to efficiently introduce siRNA, resulting in effective gene knock down in LSPCs. After isolation of LSPCs from primary patient samples, we showed that electroporation of these cells does not affect cell viability significantly. Further, using siGLO green transfection indicator, we show that RNA is introduced into the nucleus of these cells. siRNA transfection leads to efficient knockdown of target genes and has subsequent biological relevant activity. We have identified a method to effectively knock down genes in leukemia stem and progenitor cells, opening up new avenues to examine LSPC biology in human specimens.

DOI: https://doi.org/10.1101/2025.09.17.676969
Exp Hematol. 2025 Sep 18. pii: S0301-472X(25)00538-7. [Epub ahead of print] 105249

Three-dimensional Genome Reorganization in Hematopoietic Stem Cells.

Akihiro Nakajima, Keisuke Kirito, Mio Nakanishi, Naoya Takayama.

  Hematopoietic stem cells (HSCs) possess unique characteristics that distinguish them from other hematopoietic progenitor cells, including self-renewal capacity, multipotency, stress response, metabolism, and deep quiescence. Recent advances have significantly enhanced our understanding of the epigenomic states that define these properties. HSCs undergo profound changes in their three-dimensional (3D) genome reorganization throughout development, differentiation, and responses to stimuli. Recent advancements in chromatin conformation capture techniques that require only a small number of cells have provided detailed insights into these dynamic processes. This review explores the latest discoveries in the 3D genome reorganization in HSCs, with a focus on chromatin remodeling during key transitions, including fetal-to-adult development, quiescence-to-activation, differentiation, and aging. We discuss the roles of key transcription factors, epigenetic modifiers, and structural proteins in shaping the 3D genome landscape. Additionally, we examine how alterations in the 3D genome organization impact HSC function and dysfunction in hematological disorders. Finally, we highlight future directions in this rapidly evolving field, emphasizing the potential implications of 3D genome research for targeted therapies in hematology.Teaser Abstract: Hematopoietic stem cells (HSCs) are defined by self-renewal, multipotency, stress response, metabolism, and quiescence. Advances in chromatin conformation capture reveal how their 3D genome organization changes during development, activation, differentiation, and aging. This review covers chromatin remodeling, key transcription factors, epigenetic modifiers, and structural proteins in shaping HSC genome architecture, and how its disruption contributes to hematological disorders, highlighting therapeutic prospects.

Keywords:  Hematopoietic stem cells; chromatin; genome reorganization

DOI:  https://doi.org/10.1016/j.exphem.2025.105249
Nat Commun. 2025 Sep 26. 16(1): 8476

EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers.

Marija Maric, Sandra Segura-Bayona, Raviprasad Kuthethur, Tohru Takaki, Valerie Borel, Tyler H Stanage, Miroslav P Ivanov, Nishita Parnandi, Graeme Hewitt, Rhona Millar, Carmen S Fonseca, Harshil Patel, Miriam Llorian, Scott Warchal, Michael Howell, Arnab Ray Chaudhuri, Panagiotis Kotsantis, Simon J Boulton.

Exonuclease EXO1 performs multiple roles in DNA replication and DNA damage repair (DDR). However, EXO1 loss is well-tolerated, suggesting the existence of compensatory mechanisms that could be exploited in DDR-deficient cancers. Using CRISPR screening, we find EXO1 loss as synthetic lethal with many DDR genes somatically inactivated in cancers, including Fanconi Anaemia (FA) pathway and BRCA1-A complex genes. We also identify the spliceosome factor and tumour suppressor ZRSR2 as synthetic lethal with loss of EXO1 and show that ZRSR2-deficient cells are attenuated for FA pathway activation, exhibiting cisplatin sensitivity and radial chromosome formation. Furthermore, FA or ZRSR2 deficiencies depend on EXO1 nuclease activity and can be potentiated in combination with PARP inhibitors or ionizing radiation. Finally, we uncover dysregulated replication-coupled repair as the driver of synthetic lethality between EXO1 and FA pathway attributable to defective fork reversal, elevated replication fork speeds, post-replicative single stranded DNA exposure and DNA damage. These findings implicate EXO1 as a synthetic lethal vulnerability and promising drug target in a broad spectrum of DDR-deficient cancers unaddressed by current therapies.

DOI: https://doi.org/10.1038/s41467-025-63349-7
Sci Rep. 2025 Sep 23. 15(1): 32679

Detection of minimal residual disease in circulating cell-free DNA in acute myeloid leukemia.

Charlotte Sommer, Hildegard I D Mack, Madeleine C Killer, Petra Ross, Andrea Nist, Thorsten Stiewe, Andreas Neubauer, Cornelia Brendel, Elisabeth K M Mack.

  Minimal/measurable residual disease (MRD) in Acute Myeloid Leukemia (AML) is defined as persistent leukemic cells below cytomorphological detection threshold. Next generation sequencing (NGS) of circulating cell-free DNA (cfDNA) to profile cancer-associated mutations has been shown to allow for quantification of disease burden in solid tumors and has also been suggested to enable minimally invasive follow-up of AML patients. In this pilot study we investigated the technical sensitivity and potential prognostic implications of cfDNA-based MRD monitoring in AML after allogeneic stem cell transplantation in comparison to donor chimerism analysis or, respectively, after consolidation chemotherapy. 75 cfDNA samples from 29 patients were analyzed by targeted NGS using a commercially available 10- or 37-gene hotspot panel (VariantPlex Core AML or Core Myeloid panel, ArcherDx). Patients' leukemias exhibited 1-7 mutations as determined by routine diagnostics. Only previously identified mutations were considered for MRD evaluation. cfDNA was isolated in sufficient amounts for NGS from all samples (total yield 24 ng-5.2 µg). The sensitivity of variant detection increased with higher overall read count and higher mutation-specific coverage (variant allele frequency [VAF] range 0.08-100%). At least one previously known mutation was identified in 32/55 samples (58%, VAF 0.08-78.04%) which were taken during hematological complete remission (CR) in both patients after allogeneic stem cell transplantation (aHSCT) and patients after consolidation chemotherapy. In patients after aHSCT (n = 25), at least one previously known mutation was detected in 16/29 cfDNA samples (55.1%, VAF 0.08-6.7%) obtained when donor chimerism was ≥ 90% and in 6/6 samples (100%, VAF: 0.88-63.77%) with reduced donor chimerism. Probability of progression-free survival 17 months after aHSCT in patients with donor chimerism ≥ 90% but mutation-positive cfDNA was 64% compared to 100% in patients with undetectable MRD. In patients after consolidation chemotherapy, cfDNA was positive in all samples taken during CR (n = 4; VAF 0.26-29.84%) and non-CR (n = 4; VAF 8.46-100%). Our results indicate that NGS of cfDNA is suitable for MRD monitoring in AML and offers higher sensitivity for detecting residual leukemic cells than chimerism analysis in patients after aHSCT. Further studies are needed to evaluate clinical relevance of MRD status as determined in cfDNA.

Keywords:  Acute myeloid leukemia; Cell-free DNA; Minimal residual disease; Next-generation sequencing

DOI:  https://doi.org/10.1038/s41598-025-20589-3
Haematologica. 2025 Sep 25.

Loss of life expectancy in patients with myeloproliferative neoplasms in Sweden.

Yuliya Leontyeva, Anna Ravn Landtblom, Malin Hultcrantz, Mats Lambe, Hannah Bower, Paul C Lambert, Therese M-L Andersson.

Myeloproliferative neoplasms (MPN) are chronic bone marrow malignancies. While the prognosis is generally good, patients can face complications leading to reduced life expectancy. However, no population-based studies have quantified the life expectancy (LEC) and loss in life expectancy (LLE) following MPN. In this population-based study, we included individuals diagnosed with MPN in Sweden aged 50 and older between 2002 and 2021, with follow-up until 2022. We used flexible parametric relative survival models with a period analysis (2012-2021) to estimate LEC and LLE. We also estimated 15-year restricted mean survival time (RMST) and the loss in 15-year restricted mean survival time (LRMST) for each MPN subtype: polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The average LEC was 11.4 (95% CI, 11.2-11.7) and LLE was 4.3 years (95% CI, 4.1-4.6). For the MPN subtypes, the average 15-year LRMST was 1.8 (95% CI, 1.7-2.0) in PV, 1.3 (95% CI, 1.1-1.4) in ET, and 4.4 years (95% CI, 4.0-4.8) in PMF. Our study shows that life expectancy is lower in all MPN subtypes compared to the general population. By quantifying LEC and LLE, our research offers insights into the impact of MPN on an individual's lifespan beyond the diagnosis.

DOI: https://doi.org/10.3324/haematol.2024.286697
Nature. 2025 Sep 24.

Reprogramming neuroblastoma by diet-enhanced polyamine depletion.

Sarah Cherkaoui, Christina S Turn, Yuan Yuan, Wenyun Lu, Lifeng Yang, Matthew J McBride, Caroline Eigenmann, George E Allen, Olesya O Panasenko, Lu Zhang, Annette Vu, Kangning Liu, Yimei Li, Om H Gandhi, Lea F Surrey, Sandra D Kienast, Sebastian A Leidel, Michael Wierer, Eileen White, Joshua D Rabinowitz, Michael D Hogarty, Raphael J Morscher.

Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity5. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.

DOI: https://doi.org/10.1038/s41586-025-09564-0