bims-tremyl 2025-07-27 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2025–07–27
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy.
CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis.
Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML.
Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia.
Clonal haematopoiesis to clonal cytopenias: unravelling disease evolution over time.
Longer time from diagnosis to initiation of hypomethylating agents plus venetoclax for acute myeloid leukemia does not worsen survival: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND).
Gemtuzumab ozogamicin in first-line treatment of CBF-AML: insights from a retrospective multi-center analysis.
Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.
Clonal hematopoiesis in myeloid malignancies and solid tumors.
Clonal hematopoiesis in AML long-term survivors: Risk factors and clinical consequences.
Impact of graft-versus-host disease prophylaxis on second primary malignancies after allogeneic haematopoietic stem cell transplantation.
CHK1-S, a splicing variant of CHK1, suppresses chronic myeloid leukemia.
The ubiquitin ligase Triad1 influences myeloid leukemogenesis by regulating the integrated stress response.
5-Azacytidine and decitabine induce C > G transversions in both murine and human cells.
QRISK3 score is predictive of thrombotic risk in patients with myeloproliferative neoplasms.
Single-cell transcriptomics reveal individual and cooperative effects of trisomy 21 and GATA1s on hematopoiesis.
Cardiotoxicity in patients with acute myeloid leukaemia following anthracycline-containing chemotherapy: A population-based matched cohort study.
Clinical, morphological and genetic characteristics of patients with concurrent presence of JAK2 V617F and BCR::ABL1.
Molecular taxonomy of MDS/CMML patients influences responses to hypomethylating agents and clinical outcomes.
Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.
Guadecitabine improved relapse-free survival in high-risk acute myeloid leukemia and myelodysplastic syndrome patients after transplant: phase II results from a single center.
CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.
Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms.
CD123-targeting immunotherapeutic approaches in acute myeloid leukaemia.
Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells ameliorate xenogeneic graft-versus-host disease.
Deubiquitinase USP6 stabilizes oncogenic RUNX1 fusion proteins to promote the leukemic potential and malignant progression.
Targeting NLRP1-CCL8 axis in the leukaemic niche suppresses AML via inhibition of PI3K-AKT signalling.
Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1.
A Simple and Efficient Method for the Robust Expansion of Human ILC2s to Prevent Acute GvHD.
Irradiation- and busulfan-free stem cell transplantation in Fanconi anemia using an anti-CD117 antibody: a phase 1b trial.
ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche.

Leukemia. 2025 Jul 21.

Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy.

Alexandre Bazinet, Sanam Loghavi, Yue Wei, Alex Bataller, Koji Sasaki, Naszrin Arani, Faezeh Darbaniyan, Kelly Chien, Danielle Hammond, Ian Bouligny, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guilin Tang, Samuel Urrutia, Tapan Kadia, Courtney DiNardo, Naval Daver, Nicholas Short, Ghayas Issa, Naveen Pemmaraju, Elias Jabbour, Sa A Wang, Wei Wang, Gautam Borthakur, Carlos Bueso-Ramos, Farhad Ravandi, L Jeffrey Medeiros, Hagop Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo.

Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (n = 371) and showed that EP MDS (n = 67, 18%) are characterized by higher TP53 (multihit TP53: 36% vs 17%, p = 0.004), BCOR and WT1 and lower ASXL1 and SRSF2 mutation frequencies compared to non-EP (NEP) MDS (n = 304, 82%). TP53-mutant variant allele frequencies and allelic states correlated with erythroid population expansions. EP MDS was characterized by 3 genetic subgroups with distinct survival (TP53 mutant: 11.4 months; splicing mutant: not reached; not otherwise specifiable (NOS): 19.5 months, p < 0.001). EP MDS had a higher incidence of leukemic transformation (32% vs 12%, p = 0.040) and worse survival (8.3 months vs not reached, p = 0.041) after HMA-venetoclax therapy among 112 HMA-venetoclax-treated MDS patients. Expansion of erythroid populations during venetoclax failure was observed in 11 (33%) patients. EP MDS had higher BCL-XL expression levels at the RNA and protein levels compared to NEP MDS. These data support the dynamic assessment of erythroid predominance in MDS and warrant evaluation of BCL-XL inhibitors in these patients.

DOI: https://doi.org/10.1038/s41375-025-02711-6
Blood. 2025 Jul 23. pii: blood.2024026271. [Epub ahead of print]

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis.

Yuanyuan Ji, Yi Huang, Toby Thomas, Eda Gozel Kapti, Reiko Tachibana, Jacob Alan Lark, Iryna Berezniuk, Liang Guo, Mohamed A E Ali, Karin Mims, Benjamin Kroger, Wenhuo Hu, Christopher Y Park, Stephen S Chung.

Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their self-renewal capacity during proliferative stress and leukemogenesis remain unknown. Here we show CD99, a protein upregulated in leukemia stem cells (LSCs) in acute myeloid leukemia (AML), is required for the self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, these studies demonstrate that similar to HSCs, LSCs depend on maintenance of tightly regulated protein synthesis rates.

DOI: https://doi.org/10.1182/blood.2024026271
Blood Adv. 2025 Jul 24. pii: bloodadvances.2025016399. [Epub ahead of print]

Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML.

Pau Montesinos, Dylan M Marchione, Christian Récher, Michael Heuser, Susana Vives, Ewa Zarzycka, Jianxiang Wang, Marta Riva, Rodrigo T Calado, Andre C Schuh, Su-Peng Yeh, Adriana E Tron, Jianan Hui, Diego A Gianolio, Sung Choe, Prapti A Patel, Stéphane De Botton, Courtney D DiNardo, Hartmut Döhner.

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (N=73) or placebo-azacitidine (N=75). Median OS was significantly longer with ivosidenib (29.3 months; 95% CI 13.2, not reached) than with placebo (7.9 months; 95% CI 4.1, 11.3; hazard ratio 0.42 [0.27, 0.65]; p<.0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; p=.0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML. ClinicalTrials.gov registration ID: NCT03173248.

DOI: https://doi.org/10.1182/bloodadvances.2025016399
Blood. 2025 Jul 23. pii: blood.2025028993. [Epub ahead of print]

Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia.

Masayuki Umeda, Ryan Lea Hiltenbrand, Nicole L Michmerhuizen, Juan M Barajas, Melvin E Thomas, Bright Arthur, Michael P Walsh, Guangchun Song, Jing J Ma, Tamara Westover, Amit Kumar, Petri Pölönen, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore Nicola Bertuccio, Martina Pigazzi, Shondra M Pruett-Miller, Stanley B 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 such as acute myeloid leukemia (AML), T-acute lymphoblastic leukemia (T-ALL), or myelodysplastic syndrome/neoplasms (MDS) associated with 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 (AMKL) with RB1 loss or T-ALL with NOTCH1 mutations. CUT&RUN profiling of in vitro cord blood CD34+ cell (cbCD34) models of major NUP98 fusions revealed that NUP98 fusion oncoproteins directly regulate differentiation-related genes contributing to the disease phenotypes, represented by NUP98::KDM5A binding to MEIS2 or GFI1B for megakaryocyte differentiation. In patient samples, NUP98-fusion oncoprotein binding patterns are heterogeneous, potentially shaped by somatic mutations and differentiation status. Using cbCD34 models and CRISPR/Cas9 gene editing, we show that RB1 loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereas WT1 frameshift mutations skew differentiation toward dormant lymphoid-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells, providing evidence for NUP98-rearranged leukemia phenotypes affected by cooperating alterations. NUP98::KDM5A cbCD34 models with RB1 or WT1 alterations have different sensitivities to menin inhibition, suggesting that cellular differentiation provides stage-specific menin dependencies and resistance mechanisms that can be leveraged for future treatment strategies for NUP98-rearranged leukemia.

DOI: https://doi.org/10.1182/blood.2025028993
Lancet Haematol. 2025 Jul 17. pii: S2352-3026(25)00137-1. [Epub ahead of print]

Clonal haematopoiesis to clonal cytopenias: unravelling disease evolution over time.

Kristina Kirschner, Yael Kusne, Catherine Cargo, Mrinal M Patnaik.

Clonal haematopoiesis refers to the presence of somatic mutations in haematopoietic stem and progenitor cells, accompanied by the expansion of high-fitness clones over time. Age-related clonal haematopoiesis arises from ageing-related DNA damage and is associated with haematological neoplasms and coronary artery disease. Genotoxic therapies can promote the selection of somatic mutations, leading to therapy-related clonal haematopoiesis. Clonal haematopoiesis in acquired or inherited bone marrow failure syndromes and germline predispositions leads to clonal expansion, where fitness constraints on haematopoietic stem cells drive mutation acquisition. When clonal haematopoiesis occurs in the context of persistent unexplained cytopenias, with somatic mutations driving haematopoietic dysfunction, it is referred to as clonal cytopenias of undetermined significance (CCUS). CCUS is a precursor to myeloid neoplasms, with variable progression rates. In this Review, we summarise the current state of knowledge, offering critical insights into the molecular evolution of, and diagnostics and risk assessment for clonal haematopoiesis and CCUS. We highlight the interplay between ageing and environmental factors in the progression to haematological neoplasms and discuss challenges for risk stratification and disease monitoring.

DOI: https://doi.org/10.1016/S2352-3026(25)00137-1
Haematologica. 2025 Jul 24.

Longer time from diagnosis to initiation of hypomethylating agents plus venetoclax for acute myeloid leukemia does not worsen survival: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND).

Samuel J Yates, Julian J Weiss, Abigail Sneider, Emily Geramita, Guru Subramanian Guru Murthy, Talha Badar, Annie Im, Chenyu Lin, Wei Cheng, Yasmin Abaza, Alok Swaroop, Eric S Winer, Mark R Litzow, Ehab L Atallah, Anand Ashwin Patel, Rory M Shallis.

A diagnosis of acute myeloid leukemia (AML) has been considered an oncologic emergency. However, the prevailing wisdom to quickly administer AML-directed therapy is often in conflict with the time needed to complete the evaluation of actionable AML disease biology. Previous studies in intensively treated patients reported that time from date of diagnosis to treatment start date (TDT) did not impact survival outcomes. We conducted a US-based, multi-center, retrospective cohort study assessing the impact of TDT on overall survival (OS) in patients with newly diagnosed AML treated with hypomethylating agents (HMA) + venetoclax at 8 participating academic centers. 488 patients were included with a median age of 76 years. Patients had favorable (47.6%), intermediate (22.8%), and adverse (29.6%) risk disease by the 2024 European LeukemiaNet (ELN) 2024 less-intensive risk classification. Median TDT for the cohort was 9 days (IQR: 5-17). Those with TDT.

DOI: https://doi.org/10.3324/haematol.2025.288085
Leukemia. 2025 Jul 21.

Gemtuzumab ozogamicin in first-line treatment of CBF-AML: insights from a retrospective multi-center analysis.

Julian Ronnacker, Philippe J Muller, Jan-Henrik Mikesch, Sven Zukunft, Barbora Weinbergerová, Jiří Šrámek, Jan Valka, Jan Novak, Pavel Zak, Tomas Szotkowski, Zdenek Koristek, Carolin Krekeler, Julia M Unglaub, Tim Sauer, Leo Ruhnke, Sabrina Kraus, Judith Schaffrath, Lutz P Müller, Sabrina Kaes, Dirk Niemann, Lars Fransecky, Patrick P Hess, Martina Crysandt, Edgar Jost, Joana Millo, Johannes Gaertner, Roland Repp, Madlen Jentzsch, Lea Hoppe, Stefan Klein, Franziska Modemann, Nina Michalowski, Klaudia Fischbach, Wolfgang Blau, Marion Ruhs, Markus Ritter, Julian Lohmeyer, Björn Steffen, Sarah Hauser, Martin Kaufmann, Stefan W Krause, Ricarda Knabe, Karsten Spiekermann, Hubert Serve, Uwe Platzbecker, Claudia D Baldus, Carsten Müller-Tidow, Georg Lenz, Hans Christian Reinhardt, Jirí Mayer, Martin Bornhäuser, Christoph Röllig, Christoph Schliemann, Maher Hanoun.

The addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy (IC) has become a mainstay in treating patients with core binding factor acute myeloid leukemia (CBF-AML). However, evidence for the efficacy of GO in this particular subgroup is primarily based on meta-analytic data from different trials conducted more than a decade ago. In this registry-based study, we evaluated the impact of adding GO to IC in 265 CBF-AML patients from the SAL, AMLCG, and CELL cooperative study groups. Patients receiving GO had a 2-year overall survival of 90% compared with 80% in those without GO (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.21-0.95, P = 0.036) and a 2-year event-free survival of 51% versus 36% (HR 0.69, 95% CI 0.48-0.99, P = 0.046). While complete remission rates in GO vs. non-GO patients were comparable (89% vs. 90%, P = 0.81), more GO patients achieved measurable residual disease-negative remission (77% vs. 49%, P < 0.001), resulting in numerically reduced cumulative incidence of relapse (HR 0.67, 95% CI 0.43-1.02, P = 0.06). Despite delayed platelet recovery, high-grade toxicities were not increased in GO-treated patients. These findings support the integration of GO into treatment protocols for IC-eligible patients with CBF-AML.

DOI: https://doi.org/10.1038/s41375-025-02700-9
Cell Stem Cell. 2025 Jul 10. pii: S1934-5909(25)00256-5. [Epub ahead of print]

Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.

Infencia Xavier Raj, Won Kyun Koh, Jessica Harrison, Christine R Zhang, Barbara Soares, Roberta Amato, Aishwarya Krishnan, David R O'Leary, Hassan Bjeije, Tyler M Parsons, Wentao Han, Andrew L Young, Ting Wang, Luis F Z Batista, Grant A Challen.

  DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of Dnmt3a-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. Dnmt3a-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. Dnmt3a-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for DNMT3A mutations in regulating HSC longevity that is unrelated to DNA methylation function.

Keywords:  DNA methylation; DNMT3A; hematopoietic stem cell; telomerase; telomere

DOI:  https://doi.org/10.1016/j.stem.2025.06.010
Nat Cancer. 2025 Jul 18.

Clonal hematopoiesis in myeloid malignancies and solid tumors.

Xiurong Cai, Robert L Bowman, Jennifer J Trowbridge.

Clonal hematopoiesis (CH) results from clonal expansion of hematopoietic stem cells. In specific contexts, CH is linked with an increased risk of blood cancers and mortality in individuals with solid tumors. To understand the mechanisms and clinical relevance of this association, it is crucial to explore the reciprocal relationship between CH and cancer. Here, we provide an updated summary of the mechanisms known to drive CH in blood cancers and solid tumors. In addition, we review proposed strategies to intercept CH and examine their impact on solid tumor-directed therapies, including immunostimulatory therapies.

DOI: https://doi.org/10.1038/s43018-025-01014-0
Hemasphere. 2025 Jul;9(7): e70183

Clonal hematopoiesis in AML long-term survivors: Risk factors and clinical consequences.

Simon M Krauß, Eva Telzerow, Daniel Richter, Anna S Moret, Maja Rothenberg-Thurley, Cristina Sauerland, Anne Weigert, Alessia Fraccaroli, Johanna Tischer, Frank Ziemann, Katharina S Götze, Wolfgang E Berdel, Bernhard Wörmann, Utz Krug, Jan Braess, Pia Heussner, Wolfgang Enard, Wolfgang Hiddemann, Karsten Spiekermann, Dennis Görlich, Uwe Platzbecker, Klaus H Metzeler.

Clonal hematopoiesis (CH) is common in the general population and associated with various health risks, but its prevalence and clinical implications in acute myeloid leukemia (AML) long-term survivors (LTS; ≥5-year survival) are unknown. We analyzed CH in 373 AML-LTS with a median 11.6-year follow-up from diagnosis using a sensitive targeted sequencing assay based on single-molecule molecular inversion probes. CH variants were detected in 61.9% of survivors, with 26% having small-clone CH (SC-CH, variant allele frequency (VAF) < 2%) and 35.9% CH of indeterminate potential (≥2% VAF). CH was more prevalent in survivors treated with chemotherapy only (75.7%) compared to those who received allogeneic stem cell transplantation (alloSCT, 54.0%) and to age group-matched healthy controls. In chemotherapy-treated survivors, CH prevalence increased with age, whereas in alloSCT recipients, it most closely associated with hematopoietic age (i.e., the sum of donor age and time since transplantation). The variant spectrum also differed by treatment, with TP53 and PPM1D variants being more common in the chemotherapy group. CH variants ≥10% VAF associated with increased risks of diabetes in alloSCT recipients and secondary neoplasms in chemotherapy-treated survivors. This study provides insights into the high prevalence and potential clinical relevance of CH in AML-LTS.

DOI: https://doi.org/10.1002/hem3.70183
Br J Haematol. 2025 Jul 19.

Impact of graft-versus-host disease prophylaxis on second primary malignancies after allogeneic haematopoietic stem cell transplantation.

Nihar Desai, Eshrak Al-Shaibani, Tommy Alfaro-Moya, Arjun D Law, Wilson Lam, Mats Remberger, Ivan Pasic, Igor Novitzky-Basso, Auro Viswabandya, Dennis D Kim, Rajat Kumar, Jeffrey H Lipton, Jonas Mattsson, Fotios V Michelis.

  Second primary malignancies (SPMs) are a well-recognized late complication of allogeneic haematopoietic stem cell transplantation (HSCT). This study aims to evaluate the impact of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) combination on the incidence of SPMs, compared to other graft-versus-host disease (GvHD) prophylactic regimens. Among 1418 evaluable patients with a median follow-up of 6125 person-years, 138 patients developed an SPM. The cumulative incidence at 5 years was 10.6% (95% CI: 9-13). The use of ATG-PTCy was independently associated with a reduced risk of developing SPM (Hazard Ratio [HR], 0.65; p = 0.02), while older patient age (HR, 1.10; p = 0.03) and moderate-to-severe chronic GvHD (HR, 1.54; p = 0.02) were associated with an increased risk of SPM. Compared to the general population, HSCT recipients were 2.45 times more likely to develop a malignancy (p < 0.01). The 3-year overall survival from the time of SPM diagnosis was 69.8% (95% CI: 61-77) with haematological SPM independently associated with inferior survival (HR: 2.40; 95% CI: 1.3-4.5; p < 0.01). Fifteen patients (11%) developed more than one SPM. In conclusion, ATG-PTCy appears to reduce the risk of SPM post-HSCT. Active surveillance and screening for SPMs in transplant survivors are of paramount importance to ensure favourable outcomes.

Keywords:  ATG; PTCy; allogeneic haematopoietic cell transplantation; chronic GvHD; second primary malignancy

DOI:  https://doi.org/10.1111/bjh.70006
Leuk Res. 2025 Jul 22. pii: S0145-2126(25)00282-6. [Epub ahead of print]156 107922

CHK1-S, a splicing variant of CHK1, suppresses chronic myeloid leukemia.

Hu Lei, Hanzhang Xu, Yingying Wang, Yingli Wu.

  Checkpoint kinase 1 (CHK1) is a crucial protein involved in the cell cycle checkpoint during the DNA damage response and is essential for sustaining leukemia cell activity. CHK1-S (excluded exon 3) is an alternative splice variant of CHK1. Here, we demonstrate that CHK1-S is highly expressed in wild-type mouse bone marrow, and the ratio of CHK1-S to CHK1 is significantly higher compared to other tissues. The BCR-ABL protein reduces the expression of CHK1-S while increasing CHK1 levels in vitro and in vivo. Furthermore, the expression of CHK1-S is significantly reduced in the bone marrow mononuclear cells of newly diagnosed chronic myeloid leukemia (CML) patients. Inhibition of BCR-ABL activity with imatinib or knockdown of BCR-ABL can restore the expression of CHK1-S in K562 cells. Additionally, restoring CHK1-S can inhibit the proliferation of K562 cells and increase the proportion of cells in the G2/M phase. Mechanistically, the splicing factors transformer 2α (TRA2A) and TRA2B are associated with the selective splicing of CHK1-S in K562 cells. Our findings demonstrate that CHK1-S functions in opposition to CHK1, acting as a suppressor of CML.

Keywords:  CHK1; CHK1-S; Chronic myeloid leukemia; TRA2

DOI:  https://doi.org/10.1016/j.leukres.2025.107922
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02334-8. [Epub ahead of print] 110484

The ubiquitin ligase Triad1 influences myeloid leukemogenesis by regulating the integrated stress response.

Hao Wang, Francis Suh, Mariafausta Fischietti, Brian Wray, Szymon K Filip, Peter A Faull, Liping Hu, Weiqi Huang, Bin Liu, Leonidas C Platanias, Elizabeth A Eklund.

  Increased expression of a set of homeodomain transcription factors, including HoxA10, characterizes an adverse prognosis subtype of acute myeloid leukemia (AML). Examples of this subtype include AML with KMT2A or MYST3/CREBBP gene rearrangements, and an AML subset with normal cytogenetics. Previously, we identified ARIH2, the gene encoding Triad1, as a HoxA10 target gene. We determined that transcriptional activation of ARIH2 by HoxA10 was necessary to terminate emergency granulopoiesis during the innate immune response, but also antagonized leukemogenesis in a murine model of KMT2A-rearranged AML. Triad1 expression progressively decreases during the latent period preceding AML in this model, and Triad1-knockdown accelerates AML development. Triad1 is an E3 ubiquitin ligase, and we found knocking down Triad1 decreased protein ubiquitination in myeloid cells. Therefore, proteins with Triad1-dependent ubiquitination might regulate leukemogenesis and/or the innate immune response. By proteomic screen, we identified Triad1-dependent ubiquitination of a set of proteins that regulate the integrated stress response (ISR), including Gcn1. The ISR prevents metabolic exhaustion during sustained inflammation by decreasing total mRNA translation and global protein synthesis, while altering the translatome to correct metabolic deficiencies and inhibit apoptosis. In cells with Triad1-knockdown, we defined a translatome consistent with ISR-activation and reversed by co-knockdown of Gcn1. Gcn1-knockdown also delayed AML development in a KMT2A-rearranged murine model, and reversed effects of Triad1-knockdown on leukemogenesis. These results suggest ISR-inhibition mediates Triad1-related leukemia suppression, and activation of the ISR enhances leukemogenesis in this adverse prognosis AML subtype.

Keywords:  E3 ubiquitin ligase; gene expression; innate immunity; leukemia; ubiquitination

DOI:  https://doi.org/10.1016/j.jbc.2025.110484
Leukemia. 2025 Jul 18.

5-Azacytidine and decitabine induce C > G transversions in both murine and human cells.

Ryan Bertoli, Dengchao Cao, Olivia Tuckey, Susannah Gammell, Anthony Wokasch, Yang Jo Chung, Jason M Foulks, Peter D Aplan.

5-Azacytidine (5AZA) is a DNA methyltransferase inhibitor (DNMTi) used clinically to treat myelodysplastic neoplasm (MDS), and is used off-label for a number of malignancies including acute myeloid leukemia. This cytidine analog depletes intracellular DNMT1, and it has been hypothesized that DNMT1 depletion leads to hypomethylation and de-repression of methylated tumor suppressor genes. We used a pre-clinical model of MDS to investigate the efficacy of 5-azacytidine. Unexpectedly, we found an increased frequency of acute lymphoid leukemia (ALL) in 5AZA treated mice. Whole exome sequencing (WES) revealed a large number of C > G transversions in 5AZA treated mice, including genes known to be important for ALL such as Chd4, Ikzf1, and Trp53. Single base substitution (SBS) profiling revealed increased C > G mutations in the ALL cells, with a mutation signature similar to the previously described SBS39 signature. An in vitro GEMINI (Genotoxic Mutational Signature Identified After Clonal Expansion In vitro) assay recapitulated the finding of increased C > G mutations in both murine and human cell lines. Furthermore, similar GEMINI assays revealed induction of C > G mutations in cells treated with decitabine. Taken together, these findings demonstrate that azanucleosides induce C > G mutations both in vitro and in vivo, and are linked to leukemic transformation in murine cells.

DOI: https://doi.org/10.1038/s41375-025-02670-y
Leukemia. 2025 Jul 24.

QRISK3 score is predictive of thrombotic risk in patients with myeloproliferative neoplasms.

Andrea Duminuco, Raj Vaghela, Sukhraj Virdee, Claire Woodley, Susan Asirvatham, Natalia Curto-Garcia, Priya Sriskandarajah, Jennifer O'Sullivan, Hugues de Lavallade, Deepti Radia, Shahram Kordasti, Giuseppe A Palumbo, Claire Harrison, Patrick Harrington.

Thromboembolic events (TE) represent the commonest cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythaemia (ET). The QRISK3 model is a tool for predicting TE in the general population, with 7.5% recognised as a threshold to identify high-risk patients. We analyzed data of 937 patients (490 ET and 447 PV) with a median follow-up of 85 and 95 months, reporting an occurrence of 52 and 73 TE, respectively. Median QRISK3 scores at diagnosis were higher in conventional high-risk patients in both cohorts (ET; 4.2 in high-risk vs. 2.4 in low-risk, PV; 8.8 vs. 2.8, p < 0.001). During follow-up, a QRISK3 score greater than 7.5%, demonstrated potential to further stratify individuals at high risk of TE, outperforming standard risk assessments in both low and high-risk patients. Using cytoreductive treatment instead of active surveillance in patients with QRISK3 ≥ 7.5% conferred a reduced risk of thrombosis in both cohorts. Of this group, 79.7% with ET and 86.9% with PV, on cytoreductive therapy, remained thrombosis free, compared with 64.1% and 57.1% of those not receiving cytoreductive therapy (p = 0.018/0.034). QRISK3 identifies patients in whom cytoreductive therapies may be indicated, and provides a tool that allows patients to assess, monitor and reduce their cardiovascular risk.

DOI: https://doi.org/10.1038/s41375-025-02681-9
Stem Cell Reports. 2025 Jul 04. pii: S2213-6711(25)00181-X. [Epub ahead of print] 102577

Single-cell transcriptomics reveal individual and cooperative effects of trisomy 21 and GATA1s on hematopoiesis.

Kaoru Takasaki, Eric K Wafula, Jian Meng Fan, Ying Ting Sit, Sara S Kumar, David Smith, Alyssa Gagne, Peter A Gearhart, Deborah L French, Christopher S Thom, Stella T Chou.

  Trisomy 21 (T21) is associated with baseline erythrocytosis, thrombocytopenia, neutrophilia, transient abnormal myelopoiesis (TAM), and myeloid leukemia of Down syndrome (ML-DS). TAM and ML-DS blasts harbor mutations in GATA1, resulting in the exclusive expression of the truncated isoform GATA1s. Germline GATA1s mutations in individuals without T21 cause congenital cytopenias, typically without a leukemic predisposition. To dissect the developmental effects of T21 and GATA1s, we used a combination of isogenic human induced pluripotent stem cells, primary human fetal and neonatal cells, and single-cell transcriptomics to interrogate hematopoietic progenitors differing only by chromosome 21 and/or GATA1 status. Both T21 and GATA1s induced early lineage skewing, and trajectory analysis revealed that GATA1s altered the temporal regulation of lineage-specific transcriptional programs, disrupting cell proliferation and maturation irrespective of chromosomal context. These studies uncovered unexpected heterogeneity and lineage priming in early, multipotent hematopoietic progenitors and identified transcriptional and functional maturation blocks linked to GATA1s.

Keywords:  Down syndrome; GATA1; GATA1s; Trisomy 21; hematopoiesis; hematopoietic progenitors; iPSC; lineage priming; single-cell RNA sequencing; transient abnormal myelopoiesis

DOI:  https://doi.org/10.1016/j.stemcr.2025.102577
Br J Haematol. 2025 Jul 21.

Cardiotoxicity in patients with acute myeloid leukaemia following anthracycline-containing chemotherapy: A population-based matched cohort study.

Rikke Hedegaard Jensen, Christian Teglgaard, Jonas Faartoft Jensen, Joachim Baech, Claus Werenberg Marcher, Anne Stidsholt Roug, Andreas Due Ørskov, Claudia Schöllkopf, Daniel Tuyet Kristensen, Rasmus Froberg Brøndum, Marianne Tang Severinsen.

  Anthracycline-containing chemotherapy is associated with cardiovascular diseases (CVDs). While knowledge regarding the extent of cardiotoxicity in adult patients with acute myeloid leukaemia (AML) is sparse, anthracyclines remain a key component in the treatment. To address this, 1379 adult AML patients treated with anthracycline-containing chemotherapy between 2000 and 2020 were matched to 6895 comparators from the Danish background population and followed for a median of 11.8 and 12.8 years respectively. The risk of congestive heart failure (CHF) was higher in AML patients compared to the comparators throughout the entire follow-up period with adjusted hazard ratios (HRs) ranging from 15.0 (95% CI: 7.02-32.1) after 3 months to 2.68 (95% CI: 1.67-4.30) after 15 years. The risk of non-CHF CVD was initially higher in AML patients (adjusted HR: 9.16 [95% CI: 6.61-12.7] after 3 months) but converged to that of the comparators after approximately 10 years. Among AML patients, increasing age and male sex were identified as risk factors of CHF and non-CHF CVD. In summary, AML patients treated with anthracycline-containing chemotherapy had an elevated risk of CVD, particularly during the first years after treatment initiation. Increased focus on early detection and cardioprotective strategies may help mitigate the harmful effects of anthracyclines in the future.

Keywords:  acute myeloid leukaemia; anthracyclines; cardiomyopathy; cardiotoxicity; late toxicities

DOI:  https://doi.org/10.1111/bjh.70026
Sci Rep. 2025 Jul 18. 15(1): 26046

Clinical, morphological and genetic characteristics of patients with concurrent presence of JAK2 V617F and BCR::ABL1.

Nicole Naumann, Vito Dangelo, Johannes Lübke, Jakob Bresser, Volker Hagen, Jolanta Dengler, Georgia Metzgeroth, Sebastian Kreil, Tabea Hockenberger, Wolf-Karsten Hofmann, Alice Fabarius, Susanne Saussele, Nicholas C P Cross, Andreas Reiter, Juliana Schwaab.

Diagnosis and treatment of chronic myeloid neoplasms with two concurrently present driver mutations is challenging. We report on 10 JAK2 V617Fpos/BCR::ABL1pos patients in whom both mutations were identified simultaneously in 5/10 (50%) patients or in whom BCR::ABL1 appeared a median of 14 years after the primary diagnosis of JAK2 V617Fpos myeloproliferative neoplasia (MPN) in the remaining 5 patients. Granulocyte-macrophage colony-forming unit (CFU-GM) analysis demonstrated subsequent acquisition of BCR::ABL1 in a pre-existing JAK2 V617Fpos clone in 8/9 (89%) of evaluable patients. Despite the presence of JAK2 V617F in all patients, atypical BCR::ABL1 transcripts (e1a2/e19a2) in 3/9 (33%) patients and additional somatic mutations in 5/9 (56%) patients, molecular remission of BCR::ABL1 was achieved with different ABL1 TKIs (imatinib, n = 2, dasatinib, n = 2, nilotinib, n = 3) in 7/9 (78%) patients. During a total of 217 months of treatment, concomitant treatment with ABL1 TKIs and ruxolitinib did not affect dosing, efficacy or side effects. We conclude that (i) a second driver mutation might occur in chronic phase MPNs, (ii) clonality analyses largely support a common disease origin, and (iii) the dose, efficacy and safety of ABL1 inhibitors and ruxolitinib are not mutually affected by concurrent treatment.

DOI: https://doi.org/10.1038/s41598-025-11096-6
Leuk Res. 2025 Jun 28. pii: S0145-2126(25)00096-7. [Epub ahead of print]156 107736

Molecular taxonomy of MDS/CMML patients influences responses to hypomethylating agents and clinical outcomes.

Alfonso Molina, Vishesh Khanna, Alexandria Jensen, Henning Stehr, Brent Tan, Svetlana Yatsenko, Peter L Greenberg.

  We analyzed 268 patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) to determine the impact of their molecular taxonomic features on patient's clinical outcomes and responsiveness to therapy with hypomethylating agents (HMA). They were hierarchically classified via next-generation sequencing into molecular taxonomic groups based on previously described hierarchical mutational clusters (Bernard E et al, Blood 2024). The groups varied in size, molecular complexity and patient outcomes. With a median of 4 cycles of HMA-based regimens, 54 % patients were treated, with an overall response rate (ORR) of 35 % (IWG 2023 criteria). Focused evaluation of specific taxonomic subgroups demonstrated ORR in U2AF1 50 %, bi-TET2 44 %, SF3B1 40 %, TP53-multihit or CK 39 %, IDH-STAG2 36 %, SETBP1/-7 33 %, No molecular event 33 %, mNOS 28 %, CCUS-like 7 %. Notably, HMA response was not associated with International Prognostic Scoring System (IPSS-M) risk categories. The median follow-up time for the entire cohort was 4 years, with overall survival of 66 % and leukemia-free survival of 81 % at 3 years following initial diagnosis. Within the specific taxa these prognostic risk features were relatively higher for several taxonomic subgroups which were related to the patient's IPSS-M categorization. In contrast, our data demonstrated distinct differences of HMA responses within taxonomic subgroups, but without significant association between patients' HMA responses and their IPSS-M categorization. These findings indicate that molecular taxonomic classification could help refine therapeutic strategies for MDS and CMML, particularly in identifying subgroups more likely to benefit from HMA therapy.

Keywords:  CMML; HMA; IPSS-M; MDS; Molecular taxonomy; Treatment

DOI:  https://doi.org/10.1016/j.leukres.2025.107736
Leukemia. 2025 Jul 24.

Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.

Stephen J F Chong, Jolin X H Lai, Kartini Iskandar, Benedict J Leong, Chuqi Wang, Yuhan Wang, Romain Guièze, Deepika Raman, Rachel H F Lim, Catherine J Wu, Wee Joo Chng, Alice M S Cheung, Charles Chuah, Matthew S Davids, Shazib Pervaiz.

Resistance to the Bcl-2-specific inhibitor, Venetoclax (VEN), poses a therapeutic challenge in the management of chronic lymphocytic leukemia and acute myeloid leukemia. Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O2.-) levels. Validating that, augmenting intracellular O2.- in VEN-sensitive cells increases Mcl-1 phosphorylation at threonine-163 (T163pMcl-1) and protein stability via reduced Mcl-1 ubiquitination and degradation. Furthermore, redox-activated AKT/PKB is implicated in O2.--induced T163pMcl-1, as reducing intracellular O2.- or inhibiting AKT significantly decreases T163pMcl-1 and Mcl-1 accumulation, which amplifies mitochondrial apoptotic priming and restores VEN sensitivity. Importantly, combination therapy with AKT inhibitor, capivasertib, and VEN reduced VEN-resistant cells systemically and prolonged survival in a murine model. Collectively, a novel redox-dependent mechanism of Mcl-1 stability is demonstrated for the acquisition of VEN resistance, which has therapeutic implications for employing redox modulating strategies and AKT inhibitors against VEN-resistant hematologic malignancies.

DOI: https://doi.org/10.1038/s41375-025-02694-4
Haematologica. 2025 Jul 24.

Guadecitabine improved relapse-free survival in high-risk acute myeloid leukemia and myelodysplastic syndrome patients after transplant: phase II results from a single center.

Betül Oran, Peter Thall, Amin Alousi, Gheath Al-Atrash, Rohtesh Mehta, David Marin, Partow Kebriaei, Uday Popat, Roland Bassett, Qaiser Bashir, Jin Im, Amanda Olson, Jessica Jewell, Portia Smallbone, Elizabeth Shpall, Richard Champlin.

This phase 2, single-center clinical trial evaluated the efficacy and safety of guadecitabine, with or without donor lymphocyte infusion, following allogeneic stem cell transplantation (allo-SCT) in adult patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The study had three treatment cohorts based on disease status post-transplant. Cohort 1 included patients with hematological relapse after transplant (n=13). Cohort 2 consisted of patients with minimal residual disease (MRD) detected after transplant (n=18). Cohort 3 compromised of patients in remission without MRD within 100 days post-transplant (n=24). The primary objectives were to achieve morphological complete remission (CR) in cohort 1 and MRD eradication in cohort 2 within six cycles of guadecitabine. Cohort 3 patients received 12 cycles to improve relapse-free survival (RFS). In cohort 1, 21.4% of patients achieved morphological CR. In cohort 2, 47.1% achieved MRD eradication. Those who cleared MRD had a 2-year RFS of 62.5%. Cohort 3 patients had a 2-year RFS rate was 62.5% with a median follow-up of 48 months. No unexpected adverse events (AEs) occurred, and no graft failures were observed. Guadecitabine demonstrated efficacy and a favorable safety profile across all cohorts, supporting the investigations of hypomethylating agents.

DOI: https://doi.org/10.3324/haematol.2025.287628
Sci Rep. 2025 Jul 22. 15(1): 26625

CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.

Donovan Drouillard, Michael Halyko, Elizabeth Cinquegrani, Maria Poimenidou, Miracle Emosivbe, Donna McAllister, Francis C Peterson, Adriano Marchese, Michael B Dwinell.

  Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors that mobilize AML cells into the bloodstream have failed to improve patient survival, likely reflecting persistent chemokine receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the naturally occurring oligomer of CXCL12. CXCL12-LD, in contrast to wild-type or locked monomer variants, was unable to induce chemotaxis in AML cells. CXCL12-LD binding to CXCR4 decreased G protein, β-arrestin, and intracellular calcium mobilization signaling pathways, and indicated the locked dimer is a partial agonist of CXCR4. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wild-type and monomeric CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in survival, proliferation, and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist can avoid pharmacodynamic tolerance and may identify new avenues to better target GPCRs.

Keywords:  Acute myeloid leukemia; CXCR4; Cell signaling; Chemokines; GPCR; Receptor internalization

DOI:  https://doi.org/10.1038/s41598-025-12005-7
Mol Cell Biol. 2025 Jul 23. 1-24

Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms.

Diana Saleiro, Jeremy Q Wen, Markella Zannikou, Brian Lee, Ewa M Kosciuczuk, Sarah D Nehlsen, Adam Munshi, Xintong Chen, Chidera V Oku, Briana Hryhorysak, Jamie N Guillen Magaña, Jorge Heneche, Mariafausta Fischietti, Liliana Ilut, Sara H Small, Anitria Cotton, Trent Hall, Monique A Payton, Elspeth M Beauchamp, Feng Yue, Masha Kocherginsky, Elizabeth T Bartom, Ronald Hoffman, John D Crispino, Leonidas C Platanias.

  Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment approaches. We provide evidence for a key and essential role of the kinase ULK1 in MPN pathophysiology. Our studies demonstrate that genetic or pharmacological targeting of ULK1 delays substantially disease development in Jak2V617F-mutant MPN models in vivo and establish that ULK1 activity is required for transcription of genes that control hematopoietic stem cell differentiation. Pharmacological targeting of ULK1 exhibits potent therapeutic effects, resulting in reduction of early stage erythroid progenitors in spleen and bone marrow, decreased levels of hemoglobin, and reduced spleen size in MPN mouse models in vivo. Taken together, these findings provide the first evidence for a novel protumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling in MPNs and raise the potential of ULK1 as a new therapeutic target for the treatment of MPNs.

Keywords:  ULK1; myeloproliferative neoplasms; signaling; transcription regulation

DOI:  https://doi.org/10.1080/10985549.2025.2529837
Br J Haematol. 2025 Jul 24.

CD123-targeting immunotherapeutic approaches in acute myeloid leukaemia.

Alexandra Dreyzin, Noa G Holtzman, Challice L Bonifant.

  Treatment of relapsed or refractory acute myeloid leukaemia (AML) has remained a significant challenge, with limited available targeted immunotherapies. CD123, or the interleukin-3 (IL-3) receptor, has long been known as a potential target expressed on AML blasts, and a range of different approaches to targeting CD123 have been trialled with variable anti-tumour responses and toxicities observed. Here, we review the clinical outcomes of these therapies, including monoclonal antibodies and antibody-drug conjugates, as well as bispecific T-cell engager molecules and chimeric antigen receptor (CAR) T cells. We discuss the potential reasons for therapy-associated toxicity and limited efficacy, including differential antigen expression, the AML microenvironment and patient-derived T-cell fitness. To address these challenges, we highlight novel approaches to CD123 targeting currently in preclinical development. Promising new strategies include combination therapies that target CD123 and other known AML-associated antigens such as CD33 or CLL-1, NK-cell-based cell therapies, and bispecific-secreting T cells.

Keywords:  acute leukaemia; antibody therapy; cellular engineering; cellular therapies; immunotherapy; myeloid leukaemia antigens

DOI:  https://doi.org/10.1111/bjh.70019
Blood. 2025 Jul 23. pii: blood.2025028562. [Epub ahead of print]

Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells ameliorate xenogeneic graft-versus-host disease.

Lie Ma, Brent H Koehn, Michael C Zaiken, Keli L Hippen, Kyle D Smith, Jeremy R Allred, Robin L Williams, Ke Yao, Jordan Fink, Asim Saha, Benjamin Kopp, Nathaniel Payne, Renata Widelak, Angela Panoskaltsis-Mortari, Megan J Riddle, Jakub Tolar, Cindy Eide, Lily Xia, Alec Drake Witty, Amit K Mehta, Matthew Denholtz, Mehrdad Hefazi, Sophia Hani, Saad S Kenderian, Jeffrey S Miller, Jeffrey J Molldrem, Leslie S Kean, Bahram Valamehr, Bruce R Blazar.

Front-line pharmaceutical treatment for treatment of acute graft-versus-host disease (aGVHD) is not uniformly effective and has toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro generated MDSCs has been limited by the need for high MDSC:T cell ratios, multiple infusions to reduce inflammation and a relatively low peripheral blood-derived MDSC (PB-MDSCs) yield. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)-derived CD34+ cells. Compared to PB-MDSCs, iPSC-MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred on day 0 into mice undergoing GVHD lost suppressor function due to inflammasome activation and immature myeloid cell maturation1. In striking contrast to human PB-MDSCs, we show here that iMDSCs retained 95% of suppressor function in vitro despite exposure to LPS+ATP, danger-associated molecular patterns inflammasome activating stimuli released early post-transplant during conditioning and GVHD-induced injury. When transferred in vivo with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of anti-leukemia effects. iMDSC RNAseq and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS+ATP was linked to iMDSC inflammasome resistance. Taken together, these data provide a platform for translating in vitro generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses including GVHD.

DOI: https://doi.org/10.1182/blood.2025028562
Leukemia. 2025 Jul 24.

Deubiquitinase USP6 stabilizes oncogenic RUNX1 fusion proteins to promote the leukemic potential and malignant progression.

Xingya Zhang, Minjun Li, Yingqian Chen, Jiayi Liu, Jianhua Zhang, Chen Shao, Boyu Deng, Jianing Zhang, Tianrui Wang, Ji Cao, Xiaojun Xu, Qiaojun He, Bo Yang, Xuejing Shao, Meidan Ying.

RUNX1-rearranged leukemia is one of the most common subtypes of leukemia associated with genetic abnormalities. Although the majority of patients respond to chemotherapy, relapse and long-term adverse effects remain significant challenges. RUNX1 fusions, resulting from chromosomal rearrangements, are pivotal oncogenic drivers, with over 70 distinct variants identified. Therefore, elucidating their regulatory mechanisms may help to develop novel therapeutic strategies. Herein, we identify a universal deubiquitinase, USP6, that stabilizes RUNX1 fusion proteins with different partners. Importantly, USP6 is specifically upregulated in RUNX1-rearranged leukemia and strongly correlates with poor patient outcomes. Mechanistically, USP6 stabilizes RUNX1 fusions to facilitate the formation of phase separation, leading to robust transcriptional activation of the fusions. Depletion of USP6 dramatically inhibits proliferation and induces differentiation of RUNX1-rearranged leukemic cells. The marketed drug auranofin is identified as a potential USP6 inhibitor, which induces degradation of different RUNX1 fusions, further triggering myeloid differentiation and arresting xenograft tumor growth. Notably, auranofin exhibits selective therapeutic efficacy in patient-derived leukemia blasts from RUNX1-rearranged cases. Together, we not only uncover a new biological function of USP6 in regulating the transcriptional activity of RUNX1 fusions but also validate USP6 as a promising drug target and auranofin as a candidate therapy for RUNX1-rearranged leukemia.

DOI: https://doi.org/10.1038/s41375-025-02698-0
Br J Haematol. 2025 Jul 20.

Targeting NLRP1-CCL8 axis in the leukaemic niche suppresses AML via inhibition of PI3K-AKT signalling.

Xingyue Li, Qi Zhou, Xiaowen Hao, Can Cao, Seyram Yao Adzraku, Xuguang Song, Cai Sun, Xiaofeng Guo, Yue Li, Shengnan Yuan, Yujin Huang, Kailin Xu, Jianlin Qiao, Lingyu Zeng, Wen Ju.

  Bone marrow microenvironment not only plays a key role in supporting normal haematopoiesis but also plays an important role in regulating the progression of acute myelogenous leukaemia (AML). Targeting the bone marrow microenvironment will provide new targets for AML treatment. However, until now, the mechanism by which the bone marrow microenvironment promotes AML progression remains obscure. Our previous studies have found that the bone marrow microenvironment Nucleotide-binding Oligomerization Domain (NOD)-Leucine Rich Repeat (LRR)-containing Receptors (NLR) family pyrin domain containing 1 (NLRP1) plays an important role in the regulation of bone marrow endothelial cells, mesenchymal stem cell (MSC) cells and haematopoiesis, but the effect of the bone marrow microenvironment NLRP1 on AML has not been addressed. In this study, we found that niche Nlrp1 KO inhibited AML disease progression and leukaemia stem cell activity. Moreover, Nlrp1 was expressed in the bone marrow microenvironment, especially in MSC. Nlrp1 knockout in MSC inhibits the growth and proliferation of co-cultured leukaemia cells, which is related to Nlrp1 KO inhibition of Ccl8 secretion in MSC and CCL8/CCR1-mediated PI3K-AKT activation in AML cells. Our study highlights the critical role of niche NLRP1 in AML and it could be a therapeutic target for AML.

Keywords:  CCL8; NLRP1; PI3K‐AKT; acute myeloid leukaemia; bone marrow mesenchymal stem cells

DOI:  https://doi.org/10.1111/bjh.70011
Blood. 2025 Jul 23. pii: blood.2025028539. [Epub ahead of print]

Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1.

Yanxia Shi, Qian Jiang, Linxin Li, Yingying Zuo, Shuzhen Jiang, Tingting Yan, Cuifang Zheng, Shuo Zhang, Nannan Yu, Jingrong Cao, Yun Liu, Yixin Ai, Yihan Wang.

Clinical resistance or intolerance to tyrosine kinase inhibitors (TKIs) remains challenging for the treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) with central nervous system (CNS) relapse. Therapeutic options are currently limited for patients who developed the gatekeeper mutations or compound mutations. Here, we describe the preclinical profile of TGRX-678, an allosteric inhibitor designed to Specifically Target the ABL1 Myristoyl Pocket (STAMP), with potent anti-proliferative activity against the majority of ATP site mutants of BCR::ABL1 and minimal off-target cytotoxicity. When combined with ponatinib, TGRX-678 synergistically re-sensitizes the highly resistant compound mutants and T315M to growth inhibition at clinically achievable concentrations. TGRX-678 exhibits relatively high cell permeability and is not a substrate of drug efflux transporters, namely ABCB1 and ABCG2. It also demonstrates a markedly improved in vivo pharmacokinetic (PK) profile and higher oral bioavailability compared to asciminib. Importantly, TGRX-678 penetrates the blood-brain barrier (BBB) and exhibits in vivo efficacy in a murine CNS blast crisis leukemia model. Collectively, these findings suggest that TGRX-678 is a novel BCR::ABL1 allosteric inhibitor with high selectivity, potency and unique pharmacologic features, which has the potential to treat relapse or refractory CML and Ph+ ALL, even with CNS involvement.

DOI: https://doi.org/10.1182/blood.2025028539
Blood Adv. 2025 Jul 21. pii: bloodadvances.2024013609. [Epub ahead of print]

A Simple and Efficient Method for the Robust Expansion of Human ILC2s to Prevent Acute GvHD.

Danny W Bruce, Sonia J Laurie, Yan Xing, Heather E Stefanski, Keli L Hippen, Alec Wilkinson, Mark G Woodcock, James Coghill, Karen Peterson McKinnon, Bruce R Blazar, Jonathan Serody.

Reconstitution of stem cells and enhancement of the barrier function of the gastrointestinal (GI) tract is critical to the resolution of intestinal acute graft-versus-host disease (aGvHD). Previously, our group has shown in murine models that type II innate lymphoid cells (ILC2) cells generate proteins in the GI tract that enhanced GI tract barrier function and diminished the expansion and function of pro-inflammatory donor cells when given to allogeneic stem cell transplant recipients. Therefore, the infusion of donor ILC2 cells could treat or prevent GI tract acute GvHD, but for this approach to be clinically applicable, robust expansion of a homogenous population of human ILC2 cells is needed. Here, we describe a method for the rapid expansion of a uniform population of human ILC2 cells which decrease GvHD in (NOD scid gamma mouse) NSG mice. The addition of IL-4 to the culture was critical to prevent the expansion of pro-inflammatory ILC1-like cells. Our approach should allow for the evaluation of human ILC2 cells to treat therapy-resistant GI tract acute GvHD.

DOI: https://doi.org/10.1182/bloodadvances.2024013609
Nat Med. 2025 Jul 22.

Irradiation- and busulfan-free stem cell transplantation in Fanconi anemia using an anti-CD117 antibody: a phase 1b trial.

Rajni Agarwal, Alice Bertaina, Charmaine Soco, Janel R Long-Boyle, Gopin Saini, Nivedita Kunte, Lyndsie Hiroshima, Yan Y Chan, Hana Willner, Mark R Krampf, Rofida Nofal, Giulia Barbarito, Sushmita Sen, Maite Van Hentenryck, Emily Walck, Amelia Scheck, Rhonda J Perriman, Alisha Bouge, Elena Istomina, Hena Naz Din, Edna F Klinger, Jerry C Cheng, Marcin W Wlodarski, Jaap J Boelens, Judith A Shizuru, Wendy W Pang, Kenneth Weinberg, Robertson Parkman, Maria Grazia Roncarolo, Matthew Porteus, Agnieszka Czechowicz.

Current hematopoietic stem cell transplantation (HSCT) conditioning strategies cause widespread tissue damage and systemic toxicities, especially in patients with DNA-repair deficiencies such as Fanconi anemia (FA). We have developed an alternative conditioning approach that incorporates the anti-CD117 antibody, briquilimab, which targets host hematopoietic stem and progenitor cells in place of genotoxic irradiation- and busulfan-based chemotherapy. Here we report a phase 1b clinical trial in patients with FA and bone marrow failure, evaluating safety and efficacy of briquilimab-based conditioning in combination with rabbit anti-thymocyte globulin, cyclophosphamide, fludarabine and rituximab immunosuppression and T cell receptor (TCR)αβ+ T cell-depleted and CD19+ B cell-depleted haploidentical HSCT. Primary endpoints of the trial included safety and engraftment, and secondary endpoints included pharmacokinetic measures and hematological and immunological recovery. All three patients have each undergone 2 years of follow-up to complete the phase 1b analysis. No treatment-emergent adverse events or acute graft-versus-host disease was observed. Patients experienced minimal toxicities, with typical mucositis and no veno-occlusive disease. Median neutrophil engraftment was 11 days (range 11-13 days) with robust donor chimerism up to 2 years post-HSCT (99-100%), meeting the primary endpoints of the study. Briquilimab cleared in each patient before HSCT without the need for adjustment. Red blood cell, platelet and lymphocyte recovery was comparable to previous reports with TCRαβ+ T cell-depleted and CD19+ B cell-depleted grafts. All patients are alive and well with resolution of earlier chromosomal breakage abnormalities in peripheral blood lymphocytes post treatment. These data demonstrate the broad potential of this protocol in maintaining HSCT efficacy while reducing toxicity. The phase 2 trial is ongoing (ClinicalTrials.gov identifier: NCT04784052 ).

DOI: https://doi.org/10.1038/s41591-025-03817-1
Nat Commun. 2025 Jul 21. 16(1): 6580

ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche.

Hua Jiang, Denggang Fu, Santhosh Kumar Pasupuleti, Baskar Ramdas, Alan Long, Abdulraouf M Ramadan, Jinfeng Yang, Ramesh Kumar, Jessica H Hartman, B Jacob Kendrick, Ed Simpson, Hongyu Gao, Yunlong Liu, Drew Moore, Suganya Subramanian, Stefano Berto, Anilkumar Gopalakrishnapillai, Sonali P Barwe, Hongfen Guo, Nai-Kong V Cheung, Reuben Kapur, Sophie Paczesny.

Acute myeloid leukemia (AML) patients present with CD8 exhaustion signatures, and pharmacologic inhibition of checkpoints can have therapeutic benefit. The alarmin IL-33 and its receptor STimulation-2 (ST2) promote activation of tissue-regulatory T cells (Treg cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2+ Treg cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8+ T cells depletion and exhaustion. ST2 deficiency in Treg cells restores CD8+ T cell function, decreasing AML growth via retention of ST2+ Treg cells precursors in lymph nodes. AML-activated ST2+ Treg cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8+ T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed Treg cells. Engineered anti-ST2 antibodies induce ST2+ Treg cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-61647-8