bims-tremyl 2026-05-17 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2026–05–17
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Comprehensive mutational profiling and clinical outcome of adult acute myeloid leukemia patients with NUP98 rearrangement.
A ketogenesis-ferroptosis axis maintains leukemic stem cell survival and leukemia progression.
Clinical implications of RAS mutations in AML: Prognostic significance is based upon involved gene and mutation complexity.
MCL1 inhibition to enhance the efficacy of MYB targeting in pediatric acute myeloid leukemia.
Targeting PRMT9 Overcomes Venetoclax Resistance in AML by Modulating Splicing and Inhibiting Translation.
PIEZO1 is Required for Acute Myeloid Leukemia Progression and Leukemia Stem Cell Maintenance via HIF1A-SLC7A11 Axis-Mediated Ferroptosis Defense.
CDK6 inactivation counteracts CALR-mutant-induced MPN evolution and sensitizes MPN stem cells to interferon-α treatment.
Impact of hematopoietic cell transplantation and quizartinib in patients with newly diagnosed FLT3-internal tandem duplication-negative acute myeloid leukemia: results from the QUIWI study.
TP53-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition.
CRISPR-Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial.
The clinical relevance of sole loss of chromosome Y in myeloid neoplasms.
Fludarabine-Treosulfan (FT10) Conditioning in Older AML Patients Undergoing Haploidentical Transplantation: A Prospective Italian Study with External Comparison to the Haplo-UK Reduced-Intensity Conditioning Cohort.
Ferrostatin-1 and hinokitiol supplementation enhance human hematopoietic stem cell expansion in a chemically defined medium.
CSF3R-mutated chronic neutrophilic leukemia: a two-center study of 44 consecutive patients.
Comprehensive profiling of AML and T-cell states across disease stages in acute myeloid leukemia using spectral flow cytometry.
Outcomes of patients diagnosed with myelodysplastic syndrome or acute myeloid leukemia following solid organ transplantation.
Dynamic improvement of the treatment-free remission prognostic score by prolonging MR4 duration in chronic myeloid leukaemia.
MLL3 and MLL4 sustain hematopoietic stem cell multipotency by opposing a B-cell default state.
Accuracy of Diagnosis in Myeloproliferative Neoplasms With Splanchnic Vein Thrombosis (MPN-SVT).
eIF4E and Ezrin cooperate in pseudopods to drive a localized migratory translation program in acute myeloid leukemia.
A Bispecific Anti-Fluorescein × Anti-CD3 T-cell Engager in Combination with Fluoresceinated Adaptors Enables Lysis of AML Cells.
P300/CBP inhibition with inobrodib in combination with gilteritinib and venetoclax targets leukemia stem cells in epigenetic mutant AML.
Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.
A specific stem cell program and CD112 immunological axis dysfunctions underpinning monosomy 7-associated myeloid neoplasms.
Chromatin rewiring of β-globin and MYC enhancers by TGF-β1 drives defective erythropoiesis.
CHIP clinics: a practical overview of structure and function.

Leukemia. 2026 May 12.

Comprehensive mutational profiling and clinical outcome of adult acute myeloid leukemia patients with NUP98 rearrangement.

Benoit Ducourneau, Arnaud Pages, Stéphanie Struski, Matthieu Decamp, Emmanuel Raffoux, Céline Berthon, Laurène Fenwarth, Vincent Marmouset, Cécile Pautas, Thomas Cluzeau, Delphine Lebon, Madalina Uzunov, Patricio Pereyra, Maël Heiblig, Jean-Valère Malfuson, Laure Farnault, Pierre-Yves Dumas, Julia Hieulle, Sarah Bertoli, Sylvain Chantepie, Nathalie Auger, Audrey Bidet, Marie-Joelle Mozziconacci, Augustin Boudry, Isabelle Luquet, Laureen Chat, Romain Loyaux, Lina El-Mur, Emmanuelle Clappier, Claude Gardin, Mathilde Hunault, Stéphane De Botton, Arnaud Pigneux, Dominique Penther, Eric Delabesse, Raphael Itzykson, Claude Preudhomme, Hervé Dombret, Christian Recher, Nicolas Duployez, Jean-Baptiste Micol.

We report a large cohort of 95 adult patients with acute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r). Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×109/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41 y vs. 61 y), had more de novo AML (94% vs. 64%), higher rates of normal karyotypes (56% vs. 4.5%), FLT3-ITD (76% vs. 18%) and WT1 mutations (50% vs. 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 15.2 months (95% CI, 11.9-20.8) and event-free survival was 5.8 months (2-7.5). Among patients treated intensively (n = 73), age (HR = 2.7), FLT3 inhibitor therapy (HR = 0.45) and hematopoietic stem cell transplant (HR = 0.5) influenced OS in univariate analysis. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with median OS not reached and 5-year OS of 53.3%, approaching that of intermediate-risk patients.

DOI: https://doi.org/10.1038/s41375-026-02973-8
Cell Stem Cell. 2026 May 11. pii: S1934-5909(26)00153-0. [Epub ahead of print]

A ketogenesis-ferroptosis axis maintains leukemic stem cell survival and leukemia progression.

Xue Han, Kexin Wang, Weiwei Ma, Songqi Zhu, Jingjing Guan, Xiaobin Tian, Zhuangzhuang Zhao, Linjia Jiang.

  Hepatic ketogenesis generates ketone bodies as an alternative energy source during carbohydrate restriction or ketogenic diets, yet its role in non-hepatic cell types remains poorly defined. Here, we show that leukemic stem cells (LSCs) in acute myeloid leukemia (AML) exhibit elevated ketogenesis, driven by fatty acid oxidation (FAO), to produce β-hydroxybutyrate (BHB). LSCs express high levels of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis, compared with blast cells and normal hematopoietic stem cells (HSCs). Deletion of Hmgcs2 in AML cells markedly decreases BHB levels, disrupts LSC function, and impairs leukemia progression in both mouse and human AML models while largely sparing normal hematopoiesis. Mechanistically, BHB suppresses ferroptosis by limiting pro-ferroptotic phospholipid remodeling through epigenetic regulation of fatty acid desaturase 2 (FADS2). Together, these findings identify autonomous ketogenesis as a critical metabolic program that protects LSCs from ferroptotic cell death and sustains leukemia progression.

Keywords:  AML; BHB; FAO; HMGCS2; LSCs; acute myeloid leukemia; fatty acid oxidation; ferroptosis; ketogenesis; leukemic stem cells; lipid peroxidation; phospholipid remodeling; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.stem.2026.04.013
Blood Adv. 2026 May 12. pii: bloodadvances.2025018699. [Epub ahead of print]

Clinical implications of RAS mutations in AML: Prognostic significance is based upon involved gene and mutation complexity.

John N Colgan, Jack H Peplinski, Yi-Cheng Wang, Danielle C Kirkey, Logan Wallace, Yuan Feng, Li Fan, Patrick Connerty, Rhonda E Ries, Adam J Lamble, Benjamin J Huang, Todd A Alonzo, Xiaotu Ma, Katherine Tarlock, Soheil Meshinchi.

Acute myeloid leukemia (AML) is a heterogeneous disease with complex mutational profiles that lead to variable clinical outcomes. NRAS and KRAS are among the most frequently mutated genes in AML, but their clinical impact has not been well-characterized. In this cohort of over 2000 children and young adults with AML, we evaluated the role of mutations in RAS genes and mutation complexity in outcome determination. Given enrichment in KMT2A-rearranged AML (KMT2A-r), we specifically studied the significance of RAS mutations in KMT2A-r AML. Using variant calls from next generation sequencing (NGS) platforms, we identified RAS mutations in 35.1% (N=669) (NRAS, N=518; KRAS, N=216). We demonstrated that NRAS mutations were not associated with outcome in AML or in KMT2A-r AML. In contrast, KRAS mutations demonstrated inferior outcomes in AML, with enrichment of prevalence and enhancement of prognostic implications in KMT2A-r AML, including non-high risk KMT2A fusions. Additionally, we describe a complex RAS mutation cohort (Comp-RAS) characterized by two distinct RAS mutations or high variant allele frequency (VAF) RAS mutations that collectively account for 13.5% (n=90) of patients with RAS mutations. Patients with complex KRAS mutations, and those with complex RAS mutations in the KMT2A-r cohort, had a distinctly adverse outcome, and data demonstrates that Comp-RAS status drives adverse outcomes for those with KRAS mutations in the whole AML cohort.

DOI: https://doi.org/10.1182/bloodadvances.2025018699
Cell Death Dis. 2026 May 13.

MCL1 inhibition to enhance the efficacy of MYB targeting in pediatric acute myeloid leukemia.

Alexia Tsakaneli, Noelia Che, Clemence Virely, Bryony McCord, Luca Gasparoli, Aerin Loe, Kent Fung, Olivia Ciampa, Nuriye Meryem Alver, Qingyin Li, Jack Bartram, David O'Connor, Marc Mansour, Owen Williams.

Outcomes for pediatric acute myeloid leukemia (AML) have improved significantly in recent years. However, relapsed and refractory disease remains a significant problem. The chemotherapy burden experienced by these patients makes the translational development of non-genotoxic experimental therapies attractive. We previously reported that the anti-helminth drug mebendazole induces degradation of the transcription factor MYB and has potent anti-AML activity. In the present study, we use CRISPR drop-out screening to identify genes encoding the proapoptotic regulators BAK and NOXA as hits conferring resistance to mebendazole activity in AML cells. Conversely, targeting MCL1 with a BH3-mimetic significantly enhanced the anti-AML activity of mebendazole in both AML cell lines in vitro and pediatric patient-derived xenograft (PDX) AML cells ex vivo. Treatment of mice transplanted with THP-1 AML cells or aggressive infant PDX AML cells with this drug combination significantly impaired disease progression in vivo. Our data indicate that mebendazole-induced MYB degradation in combination with MCL1 targeting is a novel non-genotoxic therapeutic strategy for pediatric AML.

DOI: https://doi.org/10.1038/s41419-026-08847-2
Blood. 2026 May 12. pii: blood.2026034144. [Epub ahead of print]

Targeting PRMT9 Overcomes Venetoclax Resistance in AML by Modulating Splicing and Inhibiting Translation.

Yang Li, Xin He, Lei Zhang, Haojie Dong, Xin Wang, Yuan Che, Umesh Prasad Yadav, Meng Liu, Lianjun Zhang, Shuaishuai Ge, Guohua Wu, Yu-Hsuan Fu, Wei Chen, Ya-Huei Kuo, Liang Chen, Guido Marcucci, Shaoyuan Wang, Ling Li.

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is required for cancer cell proliferation, but whether PRMTs mediate resistance to therapy remains elusive. Here, we have performed loss-of-function screens in venetoclax-resistant (VEN-R) AML patient-derived xenograft (PDX) cells and found that PRMT9 plays a critical role in promoting VEN resistance. Specifically, VEN-R AML samples exhibited high levels of PRMT9, and PRMT9 inhibition re-sensitized the AML cells to VEN treatment. In preclinical resistant models, genetic ablation of PRMT9 synergized with VEN to eradicate AML cells. Consistently, pharmacologic inhibition of PRMT9 combined with VEN yielded similar effects in VEN-R AML mouse models. Mechanistically, PRMT9 ablation disrupted RNA splicing by inducing exon-skipping of mRNA encoding ALG13, an UDP-N-Acetylglucosaminyltransferase subunit, downregulating expression of a VEN-efflux transporter encoded by the adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) gene. PRMT9 inhibition also suppressed protein synthesis, downregulating short-lived oncoproteins, such as MCL1. These findings establish a connection between PRMT9-mediated arginine methylation and poor VEN responsiveness, also demonstrate that targeting PRMT9 may represent a viable strategy to overcome VEN resistance.

DOI: https://doi.org/10.1182/blood.2026034144
Adv Sci (Weinh). 2026 May 10. e75648

PIEZO1 is Required for Acute Myeloid Leukemia Progression and Leukemia Stem Cell Maintenance via HIF1A-SLC7A11 Axis-Mediated Ferroptosis Defense.

Tiantian Zhang, Ziyan Cao, Kexin Gao, Shuxin Yao, Yanbing Zheng, Manman Cui, Rong Yin, Guoqiang Han, Jin Hu, Chengyi Wang, Haojian Zhang.

  Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy that arises from leukemia stem cells (LSCs) transformed from normal hematopoietic stem progenitor cells (HSPCs). Compared to normal HSPCs, LSCs acquire various adaptive properties that enable their survival and regenerative capacity under environmental challenges. However, the key regulators underlying these adaptative features in AML LSCs remain largely unknown. Here, the mechanosensor PIEZO1 as a key factor in promoting acute myeloid leukemia progression and maintaining LSC stemness by HIF1A-SLC7A11 axis-mediated ferroptosis defense is uncovered. PIEZO1 deletion impairs cystine uptake and induces ROS and lipid peroxidation, causing ferroptosis of leukemia cells. Mechanistically, HIF1A mediates the function of PIEZO1 by transcriptionally regulating the expression of SLC7A11 and SLC3A2. Further, inhibition of PIEZO1 and SLC7A11 suppresses LSC function and contributes to AML treatment. In summary, this findings reveal that LSCs control cystine uptake through the PIEZO1-HIF1A-SLC7A11 axis to defend against ferroptosis, representing a unique vulnerability of LSCs.

Keywords:  PIEZO1; acute myeloid leukemia; ferroptosis; leukemia stem cells; metabolism

DOI:  https://doi.org/10.1002/advs.75648
Hemasphere. 2026 May;10 e70363

CDK6 inactivation counteracts CALR-mutant-induced MPN evolution and sensitizes MPN stem cells to interferon-α treatment.

Brian Ringhofer, Wolfram Polzer, Michaela Prchal-Murphy, Eszter Doma, Sebastian Kollmann, Elisabeth Gamper, Jonatan Kendler, Belinda S Maw, Eva Zebedin-Brandl, Juan Li, Anthony R Green, Maria-Theresa Krauth, Emir Hadzijusufovic, Daniel Ivanov, Peter Valent, Gregor Hoermann, Thorsten Klampfl, Veronika Sexl, Karoline Kollmann.

Interferon-α (IFNα) remains a potent therapeutic option for myeloproliferative neoplasms (MPNs) with an activated JAK/STAT signaling axis. However, variable patient responses highlight the need for optimized combination strategies. Recent studies suggest a link between cyclin-dependent kinase 6 (CDK6) and IFN signaling. Here, we investigated whether CDK6 inhibition might play a role in IFN responsiveness in MPN cells. Using CALR del52 knockin mice, we observed that genetic ablation of Cdk6 resulted in a reduction of spleen weight and platelet counts, while concurrently inducing interferon-associated transcriptional programs and upregulation of interferon-alpha receptor 1 (IFNAR1) on MPN cells. CDK6-deficient CALR del52 hematopoietic stem and progenitor cells (HSPCs) exhibited increased apoptosis and reduced proliferation upon inflammatory challenge compared to wild-type CALR del52 cells, positioning CDK6 as a brake on IFN signaling. Pharmacologic inhibition of CDK6 using palbociclib synergized with pegylated IFNα (pegIFNα), resulting in growth inhibition of MPN cells in vitro and in vivo. In MPN patient samples, lower CDK6 expression was associated with increased IFNAR1 expression and with stronger responses to the palbociclib/pegIFNα combination. Importantly, dose reduction of both palbociclib and pegIFNα maintained efficacy in MPN samples while minimizing cytotoxicity in control hematopoietic cells, revealing a favorable therapeutic window. These findings highlight the potential of combining CDK6 inhibition with pegIFNα to enhance anti-neoplastic effects in MPNs and support a novel potential approach to improve MPN therapy.

DOI: https://doi.org/10.1002/hem3.70363
Haematologica. 2026 May 14.

Impact of hematopoietic cell transplantation and quizartinib in patients with newly diagnosed FLT3-internal tandem duplication-negative acute myeloid leukemia: results from the QUIWI study.

Pilar Lloret-Madrid, Rebeca Rodríguez-Veiga, Juan Miguel Bergua, Jesús Lorenzo Algarra Algarra, Carmen Botella, Eduardo Rodríguez-Arbolí, Teresa Bernal, Mar Tormo, Maria Calbacho, Olga Salamero, Josefina Serrano, Victor Noriega, Juan Antonio López-López, Susana Vives, Jose Luis López-Lorenzo, Mercedes Colorado, Maria-Belén Vidriales, Raimundo García Boyero, Maria Teresa Olave, Pilar Herrera, Olga Arce, Manuel Barrios, Maria Jose Sayas, Marta Polo, Maria Isabel Gómez-Roncero, Eva Barragán, Rosa Ayala, Carmen Chillón, Maria José Calasanz, Bruno Paiva, Blanca Boluda, Ignacio Casas-Avilés, Maria José Sánchez, Carlos Rodríguez-Medina, Laida Cuevas, José Ángel Raposo-Puglia, M Carmen Mateos, Matxalen Olivares, Carmen Martínez-Chamorro, Natalia Alonso, Sandra Suárez, Irene Sánchez-Vadillo, María Solé Rodríguez, Bernardo Javier González, Antonio Martínez-Francés, Rebeca Cuello, Alfonso Fernández, David Martínez-Cuadrón, Jorge Labrador, Pau Montesinos.

QUIWI (NCT04107727) was a phase II, randomized, double-blind, placebo-controlled trial evaluating quizartinib or placebo added to induction and consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (allo-HCT), followed by maintenance, in newly diagnosed FLT3-ITD- negative acute myeloid leukemia (AML). This post hoc analysis assessed the impact of allo-HCT, modeled as a time-dependent variable, performed in first composite complete remission (CRc1) on overall survival (OS) and disease-free survival (DFS) according to treatment arm. Among 273 randomized patients, 32.2% in the quizartinib arm and 30.1% in the placebo arm underwent allo-HCT in CRc1. Quizartinib improved OS and DFS compared with placebo regardless of allo-HCT status. In Cox models with allo-HCT as a timedependent covariate, quizartinib remained associated with improved OS (HR 0.59; p=0.008) and DFS (HR 0.67; p=0.03), whereas allo-HCT was not significantly associated with OS (HR 0.91; p=0.62) and showed a numerical DFS benefit (HR 0.73; p=0.08). Multivariable analyses confirmed quizartinib as an independent favorable factor for OS (HR 0.56; p=0.046) and DFS (HR 0.60; p=0.04). No additional safety signals were observed. In patients with newly diagnosed FLT3-ITD-negative AML achieving CRc1, quizartinib improved OS and DFS in the overall population. Notably, the clinical benefit of quizartinib was observed regardless of allo-HCT, and appeared more evident in patients who did not proceed to transplant.

DOI: https://doi.org/10.3324/haematol.2026.300855
Sci Adv. 2026 May 15. 12(20): eaed7122

TP53-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition.

Jean-François Spinella, Jalila Chagraoui, Céline Moison, Isabel Boivin, Guillaume Richard Carpentier, Nadine Mayotte, François Béliveau, Vincent P Lavallée, Josée Hébert, Guy Sauvageau.

TP53-mutated acute myeloid leukemia (AML) represents a particularly aggressive and therapeutically refractory subtype of the disease. While recurrent chromosomal abnormalities such as -5/del(5q), -7/del(7q), and del(17p) are well studied in this context, additional co-occurring events remain less well defined. Using the multidimensional Leucegene dataset (~700 primary AML specimens), we identified and comprehensively characterized a distinct subset of TP53-altered AML marked by recurrent deletions on the short arm of chromosome 3 [del(3p), >20% TP53-mutated cases]. These deletions frequently co-occur with del(5q) and encompass several ribosomal protein genes (RPGs), leading to a global down-regulation of the ribosomal network and reduced protein synthesis. We show that this ribosomopathy-like phenotype is most pronounced in TP53-mutated cases with combined RPG deletions on chromosomes 3p and 5q, suggesting a cooperative oncogenic mechanism. Chemical screening identified HSP90 inhibition as a selective vulnerability in AML with low RPG expression. These findings highlight a previously unappreciated TP53-altered AML subset characterized by converging genomic and translational defects and suggest that ribosomal stress may serve as a therapeutic entry point for targeted intervention of this patient subgroup.

DOI: https://doi.org/10.1126/sciadv.aed7122
Nat Med. 2026 May 12.

CRISPR-Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial.

John F DiPersio, Guenther Koehne, Nirali N Shah, Léa Bernard, Hyung C Suh, Divya Koura, Roni Tamari, Muhammad Umair Mushtaq, Joseph Maakaron, Joseph Rimando, Vanessa E Kennedy, Sagar S Patel, Chad Hudson, Michael R Loken, Christopher A Slapak, Deborah M Lloyd, Darren A Stanizzi, Melissa M Lee-Sundlov, Sanjana Thosar, Guy Mundelboim, Guangwu Guo, Huanying Gary Ge, Bin E Li, Juliana Xavier-Ferrucio, Sharon L Hyzy, Michelle I Lin, Glen D Raffel, Brenda W Cooper.

Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR-Cas9 gene-edited allogeneic HCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In this multicenter, phase 1/2a, open-label study, adult patients with AML/MDS with high relapse risk received trem-cel after myeloablative conditioning followed by GO maintenance (0.5-2.0 mg m-2 day 1 per 28-day cycles). Patients receiving trem-cel were assessed for the primary safety endpoint of neutrophil engraftment by day 28 and secondary endpoints including time to neutrophil engraftment, incidence of graft-versus-host disease and graft failure, transplant-related mortality, percentage of CD33-negative myeloid cells and survival. Patients receiving trem-cel and GO were assessed for the additional secondary endpoints of safety of maintenance GO with trem-cel and pharmacokinetics of GO after trem-cel transplant. All 30 patients receiving trem-cel achieved the primary safety endpoint of neutrophil engraftment by day 28 with a median engraftment time of 10 days (95% confidence interval: 9-10). Nineteen patients received GO maintenance in phase 1 dose escalation (n = 15) and in phase 2 dose expansion (n = 4). The trial was stopped early, and this is the final report on the trial including the completed phase 1 portion. GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg m-2, and no prolonged high-grade cytopenias were observed. The most common adverse events were cytopenias and infections. Three cases of transplant-related mortality were observed due to renal failure, sepsis and sinusoidal obstruction syndrome, respectively. In summary, trem-cel demonstrated safe, rapid, robust engraftment, and GO maintenance was administered without prolonged hematologic toxicity. ClinicalTrials.gov identifier: NCT04849910 .

DOI: https://doi.org/10.1038/s41591-026-04362-1
Blood Cancer J. 2026 May 09. pii: 71. [Epub ahead of print]16(1):

The clinical relevance of sole loss of chromosome Y in myeloid neoplasms.

Sandra Huber, Stephan Hutter, Manja Meggendorfer, Christian Pohlkamp, Torsten Haferlach, Isolde Summerer.

DOI: https://doi.org/10.1038/s41408-026-01515-w
Transplant Cell Ther. 2026 May 11. pii: S2666-6367(26)00349-0. [Epub ahead of print]

Fludarabine-Treosulfan (FT10) Conditioning in Older AML Patients Undergoing Haploidentical Transplantation: A Prospective Italian Study with External Comparison to the Haplo-UK Reduced-Intensity Conditioning Cohort.

Vincenzo Federico, Daniele Avenoso, Kavita Raj, Hugues De Lavallade, William Wilson, Rosella Matera, Dalila Salvatore, Filippo A Canale, Manuela Merla, Corine Contento, Giulia Campagna, Giuseppe Di Renzo, Doriana Vaddinelli, Annalisa Natale, Davide Seripa, Tiziana Grassi, Francesco Saraceni, Stella Santarone, Angelo M Carella, Domenico Russo, Filippo Milano, Massimo Martino, Nicola Di Renzo.

   BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the only curative strategy for high-risk acute myeloid leukemia (AML), but its applicability in elderly and comorbid patients is limited by conditioning-related toxicity. Haploidentical HSCT (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) has expanded access to transplantation, yet the optimal reduced-intensity conditioning (RIC) regimen in this setting remains undefined. Treosulfan-based conditioning combined with fludarabine (FT10) has demonstrated a favourable toxicity profile in matched donor transplantation, but prospective data in the haploidentical platform are scarce.
METHODS: We conducted a prospective, multicentre feasibility study across eight transplant centres, enrolling patients with intermediate- or high-risk AML (ELN-2017), aged ≥65 years, with haematopoietic cell transplantation-comorbidity index (HCT-CI) ≥2, lacking an HLA-identical donor and undergoing FT10-based haplo-HSCT between June 2019 and December 2023. Conditioning consisted of treosulfan (30 g/m²) and fludarabine (150 mg/m²), followed by GVHD prophylaxis with PTCy, cyclosporine and mycophenolate mofetil. Primary endpoint was cumulative incidence of non-relapse mortality (NRM). Transplant outcomes were descriptively compared with an external reduced-intensity conditioning cohort from the prospective phase II Haplo-UK study.
RESULTS: Thirty-five AML patients were included in the FT10 cohort (median age 69 years); 58% were transplanted in complete remission (CR) with negative MRD, 22% in CR with positive MRD and 20% with active disease. Median neutrophil and platelet engraftment occurred at days +14 and +22, respectively, with full donor chimerism achieved in 94% of evaluable patients and one case of graft failure (2.8%). Cumulative incidence of NRM was 18% at day +100 and 28% at 1 year, with infections representing the leading cause of non-relapse death. Outcomes were strongly influenced by disease status at transplant: 1-year OS and LFS were 79% and 70% in patients transplanted in CR/MRD-negative, compared with 42% and 38% in those transplanted with active disease. Acute grade II-IV and chronic GVHD occurred in 13% and 40% of patients, respectively. When restricted to patients transplanted in CR, survival and relapse outcomes were broadly comparable to those observed in the Haplo-UK cohort, despite the substantially older age and higher comorbidity burden of FT10 patients.
CONCLUSIONS: In this prospective, real-world multicentre study, FT10-based haploidentical HSCT with PTCy proved feasible and effective in elderly, comorbid AML patients. These findings suggest that FT10 represents a viable conditioning option for a highly vulnerable population traditionally excluded from transplant and support further validation in larger comparative studies.

Keywords:  Acute Myeloid Leukemia (AML); Frail; Haploidentical Stem Cell Transplantation (Haplo-SCT); Treosulfan; conditioning regimen

DOI:  https://doi.org/10.1016/j.jtct.2026.05.006
Mol Ther Adv. 2026 Jun 11. 34(2): 201711

Ferrostatin-1 and hinokitiol supplementation enhance human hematopoietic stem cell expansion in a chemically defined medium.

Lushen Li, Pankaj K Mandal.

  An optimized and standardized method for ex vivo expansion of cord blood (CB) hematopoietic stem cells (HSCs) in a chemically defined medium has yet to be established. In this study, we aimed to improve ex vivo expansion of HSCs in a recently developed cytokine-free, chemically defined 3a medium. We found that the co-supplementation of the ferroptosis inhibitor ferrostatin-1 and iron chelator hinokitiol (FHK) in 3a medium significantly improves CB HSC expansion by suppressing lipid peroxidation and mitigating oxidative stress. FHK supplementation improves overall cell proliferation and promotes preferential expansion of HSCs without adversely affecting the clonogenic, engraftment, and differentiation potential of HSCs. The delayed engraftment kinetics with gradual increase in hematopoietic output further suggests that FHK treatment may preserve or expand long-term HSCs. Our findings are in alignment with recent published studies highlighting the susceptibility of HSCs to ferroptosis and corroborate the use of antioxidants to improve ex vivo expansion of HSC.

Keywords:  HSCT; HSPC; antioxidants; cells; cord blood CD34+; ferroptosis; ferrostatin-1; hematopoietic stem cells; hinokitiol; lipid peroxidation; oxidative stress

DOI:  https://doi.org/10.1016/j.omta.2026.201711
Haematologica. 2026 May 14.

CSF3R-mutated chronic neutrophilic leukemia: a two-center study of 44 consecutive patients.

Abiola B Bolarinwa, Natasha Szuber, Janick Caron-Lecuyer, Aref Al-Kali, William J Hogan, Mithun Shah, James M Foran, Talha Badar, Kaaren K Reichard, Rong He, Naseema Gangat, Cinthya J Zepeda Mendoza, Michelle A Elliott, Animesh Pardanani, Ayalew Tefferi.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.300040
Blood Immunol Cell Ther. 2025 Jun;pii: 100004. [Epub ahead of print]1(1):

Comprehensive profiling of AML and T-cell states across disease stages in acute myeloid leukemia using spectral flow cytometry.

Mhd Yousuf Yassouf, Jessica L Root, Poonam N Desai, Nicole R Vaughn, Ferdinandos Skoulidis, Hussein A Abbas, Patrick K Reville.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by clonal expansion of myeloid precursors, yet the interplay between leukemic and immune cells across disease stages remains poorly understood. Here, we used spectral flow cytometry and high-dimensional computational analyses to profile peripheral blood mononuclear cells from 72 patients with AML across 3 disease stages: newly diagnosed, remission, and relapsed/refractory. Clustering analyses identified stage-specific enrichment patterns in myeloid and lymphoid populations, with leukemic CD34+ and CD123+ cells dominating in relapsed/refractory patients and monocytic and CD45low clusters enriched in remission. T-cell profiling revealed terminal effector and senescent subsets in relapsed/refractory patients, suggesting immune exhaustion as a contributor to disease progression. Mutation-specific analyses linked TP53, DNMT3A, and NPM1 mutations to distinct enrichment patterns in both leukemic and immune populations, including increased CD71+ AML cells and altered T-cell distributions. These findings provide insights into the dynamic cellular ecosystem of AML, highlighting mutation-driven immune dysregulation and potential therapeutic targets to improve outcomes. This comprehensive profiling underscores the critical role of immune modulation in AML progression and relapse, paving the way for novel immune-targeted therapies.

DOI: https://doi.org/10.1016/j.bict.2025.100004
Haematologica. 2026 May 14.

Outcomes of patients diagnosed with myelodysplastic syndrome or acute myeloid leukemia following solid organ transplantation.

Charan Thej Reddy Vegivinti, Guillermo Montalban-Bravo, Kelly Chien, Danielle Hammond, Koji Sasaki, Alex Bataller, Ian Bouligny, Wei Ying Jen, Mahesh Swaminathan, Sanam Loghavi, Uday Popat, Guillermo Garcia-Manero, Alexandre Bazinet.

Not available.

DOI: https://doi.org/10.3324/haematol.2026.300856
Br J Haematol. 2026 May 11.

Dynamic improvement of the treatment-free remission prognostic score by prolonging MR4 duration in chronic myeloid leukaemia.

Mai Fujita, Hiroshi Ureshino.

DOI: https://doi.org/10.1111/bjh.70558
Blood. 2026 May 12. pii: blood.2025032969. [Epub ahead of print]

MLL3 and MLL4 sustain hematopoietic stem cell multipotency by opposing a B-cell default state.

Helen C Wang, Ran Chen, Wei Yang, Rohini Muthukumar, Tingting Hu, Riddhi M Patel, Emily B Casey, Elisabeth D Denby, Run Zhang, Guojia Xie, Kai Ge, Grant Challen, Jeffrey J Bednarski, Jeffrey A Magee.

Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) are sustained by networks of transcription factors and epigenetic regulators that prime lineage-specific programs yet maintain multipotency. Two epigenetic regulators, MLL3 and MLL4, play important but distinct roles in maintaining this balance. MLL3 promotes HSC differentiation, whereas MLL4 opposes differentiation. These activities are essential for both normal homeostasis and leukemia suppression, yet it is not clear how MLL3 and MLL4 regulate HSC and MPP gene expression to control HSC/MPP fate decisions. To resolve these mechanisms, we performed an extensive series of single cell genomic studies after conditionally deleting Mll3, Mll4 or both genes together. Mll3 deletion had only limited effects on HSC/MPP enhancer networks at steady state, whereas Mll4 deletion led to precocious activation of myeloid enhancers. Surprisingly, compound Mll3/4 deletion eliminated all myeloid, erythroid and megakaryocytic potential within the hematopoietic hierarchy and caused all progenitors to rapidly default to a B-cell-like identity. These changes were accompanied by widespread inactivation of HSC/MPP enhancers and superenhancers, and ectopic activation of B-cell superenhancers. Disabling MLL3/4 histone methyltransferase activity did not recapitulate the pervasive changes in cell identity that were observed when MLL3 and MLL4 were fully inactivated, indicating that MLL3 and MLL4 activate HSC/MPP enhancers independently from their enzymatic activities. Our findings show that HSC/MPP multipotency requires sustained tension between MLL3/4-dependent enhancers that maintain myeloid, erythroid and megakaryocyte potential, and MLL3/4-independent enhancers that prime B-cell identity. MLL3 and MLL4 therefore serve as critical linchpins of multilineage hematopoiesis.

DOI: https://doi.org/10.1182/blood.2025032969
Am J Hematol. 2026 May 14.

Accuracy of Diagnosis in Myeloproliferative Neoplasms With Splanchnic Vein Thrombosis (MPN-SVT).

Bharath Ram Sreedhar, Hosuk Ryou, Aoife O'Riordan, Rupen Hargreaves, Neil Chauhan, Delia Alexe, Samah Alimam, Jens Rittscher, Sabine Pomplun, Daniel Royston, Mallika Sekhar.



Keywords:  JAK2V617F with normal counts; WHO 2016 criteria; artificial intelligence; histopathology; machine learning; myeloproliferative neoplasm; myeloproliferative neoplasm—unclassifiable; splanchnic vein thrombosis

DOI:  https://doi.org/10.1002/ajh.70362
bioRxiv. 2026 Feb 23. pii: 2026.02.21.707190. [Epub ahead of print]

eIF4E and Ezrin cooperate in pseudopods to drive a localized migratory translation program in acute myeloid leukemia.

Biljana Culjkovic-Kraljacic, Leandro Marcelo Martinez, Alyssa Retiz, Samuel Perron, Naiyu Shi, Caleb Embree, Winnie Yip, Vicenta Trujillo-Alonso, Emma Lassman, Marysol Chu Carty, Kata Alilovic, Sebastien Carreno, Gail J Roboz, Monica L Guzman, Katherine L B Borden.

Aggressive subtypes of acute myeloid leukemia (AML) are characterized by increased migratory behavior and poor prognosis prioritizing the need for uncovering relevant mechanisms. While attributed to transcriptional changes, these AMLs manifest dysregulated eIF4E implicating disrupted mRNA metabolism. Here, we observed in AML mouse models, patient specimens, and cell lines that eIF4E drives motility, colonization, engraftment and AML progression. AML cells migrate utilizing Ezrin-positive pseudopods. Unexpectedly, we discovered that eIF4E interacts with Ezrin, that these physically associated factors are required and cooperated to drive an on-demand translation program in pseudopods for motility. Indeed, pseudopods were sites of eIF4E- and Ezrin-dependent translation by implementing the first method to directly mark active ribosomes in situ ( Vis ualizing T ranslation A ctivity using R iboLace, VISTA-R). Biochemically, Ezrin bound eIF4E, ribosomal components, and mRNAs consistent with our observed Ezrin-dependent modulation of protein production. This unprecedented physical coupling of motility and translation provisions migratory sites to sustain AML progression.
Highlights: eIF4E reduction impairs AML cell motility and disease progressioneIF4E-dependent motility requires EzrinEzrin binds eIF4E, transcripts encoding motility factors and active ribosomesVISTA-R enabled visualization of active ribosomes and translationally active pseudopods (T-PODs)T-PODs provide novel on-demand localized translation to sustain mobility at migratory sites.

DOI: https://doi.org/10.64898/2026.02.21.707190
Mol Cancer Ther. 2026 May 12. OF1-OF12

A Bispecific Anti-Fluorescein × Anti-CD3 T-cell Engager in Combination with Fluoresceinated Adaptors Enables Lysis of AML Cells.

Laura G Volta, Celeste Gobbi, Christian Koch, Niclas Harrer, Mara Hofstetter, Monique Maurer, Florin Schneiter, Francesco Manfredi, Christian Pellegrino, Chiara F Magnani, Timm Schroeder, Dario Neri, Markus G Manz.

Tumor-targeting antibodies, antibody-drug conjugates, and radionuclide antibody conjugates are established therapeutic tools in clinical use. Furthermore, bispecific T cell-engaging antibodies (TCEs) and chimeric antigen receptor (CAR) T cells are becoming the clinical standard of care in hemato-oncology and in some solid tissue neoplasms. To allow for on-off switching and targeting of multiple antigens, CAR T cells designed to recognize tumor-bound adaptor molecules (adaptor-CAR T cells) are now being investigated in clinical trials. We hypothesized that like adaptor-CAR T cells, a bispecific TCE recognizing CD3ε on T cells and fluorescein on tumor-bound adaptors would be able to direct T cells against target cells, potentially enabling multiplexing. We here show that a newly generated single-chain Fv-based anti-CD3 × anti-FITC construct (AdFITC-TCE) activates T cells toward acute myeloid leukemia (AML). Recognition of multiple targets through binding to fluoresceinated antibody constructs against CD33 and CD117 enables efficient tumor cell lysis in vitro. Moreover, we demonstrate that AdFITC-TCE plus fluoresceinated adaptors and T cells inhibit AML cell growth in NOD.Cg-Prkdcscid Il2rgtm1WjI/SzJ mice in vivo with similar efficacy as AdFITC-CAR T cells. Together, these data suggest that AdFITC-TCE, in combination with any given fluoresceinated binder, might be a versatile tool to activate T cells, leading to respective target cell lysis.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0985
Sci Adv. 2026 May 15. 12(20): eaec9305

P300/CBP inhibition with inobrodib in combination with gilteritinib and venetoclax targets leukemia stem cells in epigenetic mutant AML.

Melanie L Goetz, Jennifer S Romer-Seibert, Amanda M Versace, Scott Kogan, Chetan Jeurkar, Robert L Bowman, Nigel Brooks, Kris Frese, Sara E Meyer.

Acute myeloid leukemia (AML) is a fatal blood cancer with cytotoxic chemotherapy offering at best 25% 5-year survival. While targeted BCL2 and FLT3 inhibitors venetoclax and gilteritinib are used upfront in the treatment of a subset of adult patients with AML and help to extend the survival of some patients, a curative treatment combination with minimal side effects has yet to be discovered. We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of DNMT3A/FLT3-mutant AML by impairing pro-oncogenic survival and proliferation factors to effectively block leukemogenesis. This work identifies potential clinical utility of a targeted, triplet combination therapy for treatment of AML.

DOI: https://doi.org/10.1126/sciadv.aec9305
Biochem J. 2026 May 27. 483(6): 907-925

Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.

Brett R Chrest, Kelsey H Fisher-Wellman.

  Targeting mitochondrial oxidative phosphorylation (OxPhos) has become a recurring strategy in the treatment of cancer, particularly in acute myeloid leukemia (AML). Early reports suggested that leukemic blasts, and especially leukemia stem cells, depend disproportionately on mitochondrial respiration, implying a therapeutic window for systemic inhibition of the electron transport system (ETS) and OxPhos. Yet, the clinical record of broad OxPhos inhibition has been disappointing. In the present review, we argue that the pivotal question is not whether mitochondria matter for cancer, but whether specific mitochondrial processes are disproportionately essential to malignant cells compared with the organism's most OxPhos-dependent organs. We clarify what OxPhos is (and is not), emphasizing why oxygen consumption rate (OCR) is an incomplete surrogate for ATP-producing OxPhos flux and why transcriptomic 'OxPhos signatures' often confound energetic demand with compensatory responses to mitochondrial damage. We then benchmark OxPhos capacity and flux across normal tissues versus tumors, highlighting that highly oxidative organs typically operate at far higher respiratory flux than most cancers. Using the Complex I inhibitor IACS-010759 as a case study, we discuss why systemic ETS inhibition predictably collided with dose-limiting toxicity. Finally, focusing on AML, we dissect how OxPhos 'dependency' was inferred from indirect assays, how the failure to normalize for mitochondrial content may invert conclusions, and how ATP synthase reversal can masquerade as 'ATP-linked respiration.' We conclude with practical criteria for identifying mitochondrial liabilities that are targetable rather than merely essential, and we outline alternative strategies, which may better align mitochondrial biology with a realistic therapeutic index.

Keywords:  acute myeloid leukaemia; complex I; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1042/BCJ20260185
Signal Transduct Target Ther. 2026 May 11. pii: 173. [Epub ahead of print]11(1):

A specific stem cell program and CD112 immunological axis dysfunctions underpinning monosomy 7-associated myeloid neoplasms.

Anair Graciela Lema Fernandez, Carlotta Nardelli, Martina Quintini, Valeria Di Battista, Valentina Pierini, Barbara Crescenzi, Fabrizia Pellanera, Caterina Matteucci, Valentina Bardelli, Maria Crocioni, Giovanni Martino, Francesco Maria Adamo, Francesca Milano, Maria Paola Martelli, Pietro Merli, Loredana Bury, Paolo Gorello, Mattia Forcato, Franco Locatelli, Loredana Ruggeri, Cristina Mecucci.

Monosomy 7 (-7) is occurring as isolated change or in complex karyotypes in 10-20% of myeloid neoplasms with poor prognosis. Although several genes mapping at chromosome 7 have been involved in pathogenetic mechanisms, the -7 molecular landscape is not fully elucidated. Using an epi-transcriptomic approach, new biological insights emerged in monosomy 7. A private 49 stemness gene program was first identified and it included 59.2% of the targets of the homeobox transcription factors, specifically deregulated in -7 by hypermethylated intergenic enhancers. Additionally, 20.4% of the stemness program was determined by the signature generated by IKZF1/7p12.2 deficiency, responsible for upregulation of the CD112 immuno-checkpoint gene. Focusing on CD112, immunohistochemistry typically assigned its expression to bone marrow blasts and myeloid progenitors in monosomy 7. Concomitant increased expression of the inhibitory TIGIT and PVRIG receptors, and decreased expression of the activating DNAM1 receptor, significantly emerged in CD3+, and natural killer (NK) cells from patients with -7. Moreover, receptors deregulation was shown to be induced by CD34+ leukemic cells with CD112 overexpression. Development of an "ex vivo" model, that used cytotoxicity assays with primary cells from AML cases and autologous NK cells after blockade of the TIGIT and PVRIG receptors, allowed us to show enhanced cytolytic activity of NK against leukemic cells with -7. Altogether, these results first disclosed a dysfunctional TIGIT-PVRIG-DNAM1/CD112 axis in myeloid neoplasms with monosomy 7, inspiring the use of inhibitory receptors blockade to exploit the NK autologous reactivity against a still undruggable cytogenetic change of myeloid neoplasms with dismal prognosis.

DOI: https://doi.org/10.1038/s41392-026-02681-w
Nat Commun. 2026 May 13.

Chromatin rewiring of β-globin and MYC enhancers by TGF-β1 drives defective erythropoiesis.

Srinivas Aluri, Kimo Bachiashvili, Anjali Budhathoki, Jong Jin Jeong, Shanisha Gordon-Mitchell, Samarpana Chakraborty, Jung-In Yang, Srabani Sahu, Sanjay Pandey, Micheal Sandhu, Mahinder Paul, Wenjun Deng, Rahul Sanawar, Plabani Sahu, Leah Kravets, Sarah Aminov, Ritesh Aggarwal, Beamon Agarwal, Divij Verma, Gaurav S Choudhary, Tushar D Bhagat, Milagros Carbajal, Rongbao Zhao, Kith Pradhan, Shahina Maqbool, Seong-Jin Kim, Ulrich G Steidl, Aditi Shastri, Marc Raaijmakers, Andrea Pellagatti, Jacqueline Boultwood, Amittha Wickrema, Amit Verma.

Erythropoiesis is a tightly regulated process involving rapid cell proliferation with orderly differentiation to ensure production of millions of RBCs. TGF-β1 is a key regulator of erythropoiesis, however, the mechanisms via which it regulates erythropoiesis are not well elucidated. Using myelodysplastic syndromes patient samples, we show that elevated TGF-β1 and SMAD2 signaling correlates with the degree of anemia. Functional studies in primary human HSPCs demonstrate that TGF-β1 exerts a bifurcated effect - suppressing proliferation and inducing premature erythroid differentiation - both of which are rescued by clinical-stage TGFBR1 inhibitor. Through integrative RNA-seq, ChIP-seq, and Micro-C analyses, we find TGF-β1 activates β-globin LCR, driving early differentiation, while concurrently disrupting the MYC enhancer-promoter interaction to block proliferation. We validate erythropoiesis defects in vivo by performing single-cell RNA-seq in a TGF-β1 overexpressing mouse model. Overall, we show that TGF-β1/SMAD2 signaling re-wires chromatin to regulate erythropoiesis by affecting the β-LCR and MYC super enhancer regions.

DOI: https://doi.org/10.1038/s41467-026-72963-y
Blood Cancer J. 2026 May 14.

CHIP clinics: a practical overview of structure and function.

Shyam A Patel, Abhishek A Mangaonkar.

Modern knowledge about the principles of clonal hematopoiesis of indeterminate potential (CHIP) has paved way for numerous clinical efforts aimed at managing this pre-malignant condition. The emergence of various CHIP clinics across the globe attests to collaborative attempts to formalize clinical management of CHIP and its entities. However, translational science in this field is limited to date, partly due to nascent therapeutic concepts with limited understanding of natural history and longitudinal follow up. Here, we explore the structure and function of existing CHIP clinics and propose a working model to materialize future CHIP clinics at academic and community health care systems. We discuss the critical elements in conceptualizing and operationalizing CHIP clinic workflows, including pinpointing unmet clinical needs, prospective and retrospective identification of patients with CHIP, and recruitment of key CHIP clinic personnel toward creation of an effective multidisciplinary team. We underscore the clinical utility of CHIP clinics with regard to value creation in preventive hematology, real-world risk assessment using evidence-based models, provision of clinical trial enrollment opportunities, establishment of curated research registries and tissue biorepositories, and development of community outreach efforts. Finally, we shed light onto prospects of continued multi-center participation in collaborative science related to emerging therapeutic options in CHIP. These concepts may have a favorable impact on previvorship in hematology in the coming years.

DOI: https://doi.org/10.1038/s41408-026-01514-x