bims-tremyl 2026-06-21 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–06–21
25 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.
Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
Prognostic and therapeutic implications of BRAF mutations in acute myeloid leukemia.
Mutational dynamics in patients with del(5q) MDS treated with lenalidomide prior to transfusion dependency-Molecular results from the Sintrarev clinical trial.
Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS.
Distinct stem cell identities converge into shared erythroid stress in ERCC6L2 disease and Shwachman-Diamond syndrome.
Validation of ELN 2024 genetic classification in patients with AML treated with HMA-based regimens: PETHEMA registry study.
The search for safe and effective CAR-T targets in AML.
ICC/WHO-Defined and NGS-Annotated Idiopathic Hypereosinophilia (iHES/iHE): Mutations, Clinical and Treatment Details, and Predictors of Survival.
Limited prognostic value of ELN classification and relevance of molecular ontogeny in acute myeloid leukemia post myeloproliferative neoplasms: a retrospective multicenter study.
Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation.
NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS.
Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study.
Mathematical modeling of JAK2V617F clonal expansion in a general population cohort.
Targeting mitochondrial TRIP13-AIF interaction suppresses myeloid leukemia progression and overcomes drug resistance.
Systemic Mastocytosis in Adults: 2026 Update on Diagnosis, Risk Stratification and Management.
ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
Dual CDK2 and CDK4/6 inhibition suppresses Rb/E2F signaling and enhances anti-leukemic activity in acute myeloid leukemia.
Outcomes of Adolescents and Young Adults with AML Treated on Pediatric vs Adult Protocols.
Bone marrow immunosuppressive states associate with survival after guadecitabine and atezolizumab therapy in HMA-R/R MDS.
PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1.
FAP-1 loss impairs megakaryocyte demarcation membrane system and platelet function with myelofibrosis-like features.
ALDH3A2-mediated fatty acid synthesis induces ferroptosis and AML drug resistance.
Variant-specific SF3B1 mutations drive distinct splicing and mitochondrial dysfunction in myelodysplastic neoplasms.
Outcome of treatment with trametinib in adults with histiocytic neoplasms in the United Kingdom.

J Hematol Oncol. 2026 Jun 16.

Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.

Sankalp Arora, Jayastu Senapati, Indraneel Deshmukh, Prithviraj Bose, Lucia Masarova, Sanam Loghavi, Xuemei Wang, Graciela Nogueras-Gonzalez, Guillermo Montalban-Bravo, Gautam Borthakur, Courtney D DiNardo, Tapan Kadia, Lingsha Zhou, Dyana Saenz, Habiba Halim, Yesid Alvarado, Maro Ohanian, Koichi Takahashi, Nicholas J Short, Elias Jabbour, Farhad Ravandi, Guillermo Garcia-Manero, Naveen Pemmaraju, Naval G Daver.

BACKGROUND: Myelodysplastic syndrome and myeloproliferative neoplasm (MDS/MPN) overlap syndromes are characterized by the presence of features of both MDS and MPN and have a poor prognosis. We conducted a phase 2 clinical trial evaluating the combination of Azacitidine (AZA) and Ruxolitinib (RUX) in MDS/MPN, with interim analysis showing an objective response rate of 57%. Herein, we report the final analysis from this clinical trial, including long-term survival data.
METHODS: This was an open-label phase 2 clinical trial including adult patients in 2 diagnostic arms: myelofibrosis (arm 1) and MDS/MPN (arm 2). This manuscript reports outcomes of MDS/MPN patients. RUX 5-20 mg twice daily (per RUX label) was administered in 28-day cycles, and AZA 25 mg/m2 on days 1-5 was added starting cycle 4. Primary endpoint was objective response rate per the 2015 International Consortium Proposal (ICP) MDS/MPN response criteria.
RESULTS: From 5/2013 to 8/2022, 52 patients were treated with a median age of 68 years (range, 39-82). Disease subtypes were MDS/MPN-Unclassifiable in 24 patients (46%), chronic myelomonocytic leukemia in 23 patients (44%), and atypical chronic myeloid leukemia in 5 patients (10%). Majority of patients (n = 40, 77%) had intermediate-2/high-risk disease by Dynamic International Prognosis Scoring System criteria. Objective responses were attained in 30 patients (58%), with a median duration of response of 13.6 months (95% CI: 6.4-41.1). After a median follow up of 88.5 months, 13 (25%) patients are alive, with median overall survival (OS) of 26.7 months (95% CI: 16.5-52.7), 5-year OS 33%. Median OS in MDS/MPN-U and CMML was 52.7 months (5-year OS 46%) and 17.5 months (5-year OS 27%), respectively. Twelve patients (23%) underwent allogeneic stem cell transplantation; with median OS not reached, 5-year OS 51%. Transformation to acute myeloid leukemia occurred in 13 patients (25%). The most common grade 3-5 adverse events (AEs) regardless of attribution were anemia (31, 60%), thrombocytopenia (27, 52%) and pneumonia (17, 33%). AE-related treatment discontinuation occurred in only 3 patients (6%).
CONCLUSIONS: AZA-RUX therapy led to durable responses and encouraging OS in MDS/MPN with a manageable safety profile.
TRIAL REGISTRATION: NCT01787487, (clinicaltrials.gov, date: 2/6/2013).

DOI: https://doi.org/10.1186/s13045-026-01813-7
J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]

Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.

Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.

  Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.

Keywords:  Cancer; Cell biology; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI196687
Leukemia. 2026 Jun 15.

Prognostic and therapeutic implications of BRAF mutations in acute myeloid leukemia.

Darren Lee, Yazan Abu-Shihab, Kate Plas, Deedra Nicolet, Krzysztof Mrózek, Mark J Routbort, Keyur P Patel, Christopher J Walker, Jill Buss, Andrew R Stiff, Andrea Laganson, Courtney D DiNardo, Naval G Daver, Tapan M Kadia, Farhad Ravandi, Andrew J Carroll, Jonathan E Kolitz, Bayard L Powell, William G Blum, Maria R Baer, Guido Marcucci, Geoffrey L Uy, Wendy Stock, Richard M Stone, L Jeffrey Medeiros, John C Byrd, James S Blachly, Robert L Bowman, Jeffrey W Tyner, Sanam Loghavi, Ann-Kathrin Eisfeld, Linde A Miles.

Mutations in the RAS/MAPK signaling pathway are recurrent in acute myeloid leukemia (AML), primarily involving NRAS and KRAS. In contrast, mutations in the gene encoding an effector protein, BRAF, occur at relatively lower frequencies in AML and are associated with poor outcomes. To date, no comprehensive analysis has assessed the clinical and molecular characteristics of BRAF-mutated AML. In this study, we report the identification of canonical and non-canonical BRAF mutations in ~1% of 5779 consecutive clinically and molecularly fully annotated AML patients treated at two major United States Cancer Centers (50/5779 AML patients: 21 newly diagnosed AML; 9 relapsed/refractory; 20 newly diagnosed secondary AML). We performed single-cell multiomic analysis on a subset of AML samples. BRAF mutations were enriched in myelodysplasia-related AML (AML-MR), and most mutations were located outside the V600 hotspot. Single-cell multiomic profiling delineated BRAF mutation class-specific patterns of co-mutations, clonality, and immunophenotypes. Notably, BRAF mutations and other signaling co-mutation(s) could be found in the same cell, a finding that significantly diverges from prior studies of RAS-mutant AML. In this cohort, BRAF-mutant AML patients had poor overall survival with currently available treatments, including venetoclax-based regimens. Drug sensitivity data suggest possible avenues for targeted treatment of BRAF-mutated AML.

DOI: https://doi.org/10.1038/s41375-026-02996-1
Hemasphere. 2026 Jun;10(6): e70402

Mutational dynamics in patients with del(5q) MDS treated with lenalidomide prior to transfusion dependency-Molecular results from the Sintrarev clinical trial.

Sofía Toribio Castelló, Felix López-Cadenas, Claude Preudhomme, Teresa González, Angela Villaverde Ramiro, Laurène Fenwarth, Blanca Xicoy, Aline Renneville, Joaquín Sánchez-Garcia, Rosa Coll, Bohrane Slama, José Ángel Hernández-Rivas, Sylvain Thepot, Teresa Bernal, Agnès Guerci-Bresler, Raúl Azibeiro, Monica Del Rey, Katharina S Götze, Pierre Fenaux, Jesús María Hernández-Rivas, María Díez-Campelo.

Lenalidomide (Len) is the standard of care for red blood cell transfusion-dependent (TD) patients with myelodysplastic syndromes (MDS) and del(5q). A Phase III clinical trial (SintraRev) demonstrated better efficacy of early treatment with Len in anemic del(5q) MDS patients prior to TD, but clonal evolution with this approach remained unexplored. We evaluated changes in mutational profiles of non-TD del(5q) MDS patients treated with Len to assess whether early administration of Len could reduce or worsen the mutational burden in those patients. The molecular profile of patients included in the SintraRev trial was analyzed by targeted sequencing. Median follow up of patients was 60.6 months (interquartile range [IQR] 32.3-73.9). Next-generation sequencing (NGS) was available in a total of 51 patients. SF3B1 (25.5%) and TP53 (21.3%) were the most frequently mutated genes. Clonal evolution during treatment among patients receiving Len or placebo (Pcb) was markedly different, with a 41.2% reduction in predominating clones in the Len arm, while remaining stable/increase in 100% of Pcb patients after 2 years. Mutations in SF3B1 and TP53 decreased/remained stable in the Len cohort, while only DNMT3A mutations increased under cytogenetic response. Regarding disease progression, only 20% of Len patients carrying TP53 mutations developed acute myeloid leukemia (AML), similar to the Pcb group (20%). Treatment with low-dose Len in transfusion-independent del(5q) MDS reduced the mutational burden of most genes and did not promote the expansion of preexisting clones or AML progression, especially TP53-mutated clones. Early administration of Len in del(5q) MDS patients without TD may be an effective therapeutic approach with a manageable safety profile regarding clonal evolution.

DOI: https://doi.org/10.1002/hem3.70402
Blood. 2026 Jun 18. pii: blood.2025030731. [Epub ahead of print]

Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS.

He Tian Tony Chen, Pratik Joshi, Severine Cathelin, Soheil Jahangiri Tazehkand, Saeer A Adeel, Joshua Xu, Emily Tsao, Yulin Mo, David Kealy, Adam Dowle, Zaldy Balde, Marry Xuan, Dylan Gowlett-Park, Katarina Czibere, Alexandra Misura, Olga Bigun, Renato Sasso, August Lin, Noor Kundu, Dianne Chadwick, Sila Usta, Tina Khazaee, Signy Chow, Hubert Tsui, Mark D Minden, Andrew N Holding, Katherine S Bridge, Gang Zheng, Kristin Hope.

Myelodysplastic neoplasms (MDS) feature hematopoietic deficits driven in part by transcript splicing abnormalities. Thus far, such disease-driving transcripts have been identified in association with specific splicing factor mutations. However, conserved aberrant splicing-derived transcripts that drive MDS independently of mutational status remain poorly studied despite representing global therapeutic targets. Here, we characterize an MDS-associated MBD1 isoform (MBD1-L) as a novel member of this class of transcripts. Rather than originating from a mutant splicing factor, the abnormal production of MBD1-L is driven by reduced WTAP expression in MDS. Overexpression of MBD1-L in healthy human HSPCs recapitulates archetypal MDS defects, including reduced terminal GLYA+ erythroid differentiation, suppressed cell cycling and impaired in vivo reconstitution capacity during increased hematopoietic demand in xenotransplantation assays. An integrated multiomics approach assessing DNA binding of MBD1 isoforms, and resulting changes in chromatin accessibility, histone mark deposition and transcriptional changes, revealed that these defects arise from an isoform-specific switching of MBD1's binding behavior. The MBD1-L isoform refocuses MBD1-L's heterochromatin-promoting activity from methylated to unmethylated CpGs and thus enacting broad downregulation of CpG-rich promoters as well as secondary epigenetic effects mediated by its downstream target BCOR. Remarkably, we also find that directly reversing abnormal MBD1 splicing across a broad range of primary human MDS samples using nanoparticle-encapsulated ASOs enhances in vitro erythroid differentiation, supporting the utility of RNA therapies for MDS treatment. Thus, our findings demonstrate MBD1-L to be a global, disease-driving splice variant across MDS, and illustrate the potential for RNA-based therapies in the broad treatment of MDS.

DOI: https://doi.org/10.1182/blood.2025030731
Hemasphere. 2026 Jun;10(6): e70374

Distinct stem cell identities converge into shared erythroid stress in ERCC6L2 disease and Shwachman-Diamond syndrome.

Laura Langohr, Ilse Kaaja, Suvi P M Douglas, Hanna Nebelung, Jessica Koski, Ina Ikonen, Lotta Katainen, Katri Maljanen, Marja Hakkarainen, Tuulia Räisänen, Riitta Niinimäki, Sakari Kakko, Timo Siitonen, Sadiksha Adhikari, Markus Vähä-Koskela, Caroline A Heckman, Jenni Lahtela, Ulla Wartiovaara-Kautto, Esa Pitkänen, Outi Kilpivaara.

ERCC6L2 disease (ED) is a rare bone marrow failure syndrome caused by biallelic germline mutations in ERCC6L2. ED leads to the accumulation of somatic TP53 mutations, myelodysplastic syndrome, and acute myeloid leukemia (AML) with erythroid predominance and poor prognosis. While ERCC6L2 is implicated in DNA replication and repair, the transcriptomic events underlying delayed erythropoiesis and leukemic progression remain largely undefined. To delineate these processes, we leverage bulk and single-cell transcriptomics of patient fibroblasts, bone marrow, and peripheral blood across disease stages, including single-cell TP53 genotyping. We identify disease-associated erythroid dysregulation and ferroptotic stress emerging prior to TP53 mutation, highlighting an early vulnerability in ED leukemogenesis. We compare ED to Shwachman-Diamond syndrome (SDS) to reveal shared and disease-specific transcriptional programs. TP53 mutations in ED and SDS arise in hematopoietic stem and progenitor cells but do not independently drive changes in cell cycle or stress pathways during erythropoiesis, despite harboring distinct germline defects. Both diseases converge in late erythropoiesis into a stress state characterized by ferroptotic signaling, G1 arrest, and BCL2L1 upregulation. As a disease-specific pattern, ED shows aberrant erythroid priming with TP53-driven differentiation arrest shaping progression toward erythroid leukemia. Thereby, we establish the first patient-level single-cell map of ED and provide a curated resource for future work on ED, SDS, and TP53-driven leukemogenesis. Overall, our findings in pre-malignant ED offer a window into early alterations leading to high-risk leukemia.

DOI: https://doi.org/10.1002/hem3.70374
Blood Neoplasia. 2026 Aug;3(3): 100238

Validation of ELN 2024 genetic classification in patients with AML treated with HMA-based regimens: PETHEMA registry study.

PETHEMA group

The 2024 European LeukemiaNet (ELN 2024) genetic risk classification was proposed to assess prognosis in patients with acute myeloid leukemia (AML) receiving less-intensive hypomethylating agent (HMA)-based regimens. However, its applicability to real-world patients remains unclear. We retrospectively analyzed 669 adult patients with AML from the PETHEMA registry treated in routine practice with HMA monotherapy (n = 414) or HMA-venetoclax (VEN) (n = 255). Molecular profiling was performed centrally among the Programa Español de Tratamientos en Hematología (PETHEMA) laboratory network. Median age was 75 years, and 48% had secondary AML (s-AML). Across the full cohort, ELN 2024 stratified patients into prognostic groups across both regimens, but overall survival (OS) was consistently shorter with HMA monotherapy than with HMA-VEN (median OS, 6.5 vs 11.2 months). Favorable risk patients treated with HMA-VEN achieved a median OS exceeding 18.4 months, whereas adverse risk patients had an OS of 7.7 months. ELN 2024 provides meaningful stratification in nonintensive AML, especially with HMA-VEN. However, prognostic accuracy is limited in HMA monotherapy and s-AML, particularly those arising from a myeloid neoplasm (sM-AML). Incorporating cytogenetic risk and sM-AML as adverse risk improved discrimination (area under the curve at 24 months, 0.71 vs 0.76). Refinement incorporating clinical history, cytogenetics, emerging mutations, and treatment response is needed to improve risk prediction in real-world populations.

DOI: https://doi.org/10.1016/j.bneo.2026.100238
Blood Cancer J. 2026 Jun 20.

The search for safe and effective CAR-T targets in AML.

Florian Van Oers, Donovan Flumens, Simon Haentjens, Laurens Krekelbergh, Sébastien Anguille.

Acute myeloid leukemia (AML) remains a highly aggressive malignancy with limited therapeutic options and poor long-term survival. A major barrier to curative treatment is the persistence of leukemic stem cells (LSCs), a chemo-resistant population that drives relapse. Chimeric antigen receptor (CAR)-T-cell therapy has transformed the treatment of B-cell hematological malignancies. However, its application in AML has been met with significant challenges. Among the key challenges are the scarcity of AML-specific antigens and the risk of on-target/off-tumor toxicity due to shared antigen expression on normal hematopoietic stem cells (HSCs) and/or mature blood cells. Early clinical trials of CAR-T-cell therapy in AML -primarily targeting CD123, CD33, or CLL‑1- have demonstrated limited durable complete remissions and/or frequent myeloablation, underscoring the need for more selective targets. While other targets show more restricted expression profiles, they are often expressed only in a small subgroup of AML patients. In this review, we systematically evaluated 63 AML-associated antigens for which CAR constructs have been reported, using five criteria: (1) homogeneous expression across AML patients, (2) uniform expression on AML cells within individual patients; (3) presence on LSCs, (4) absence on normal HSCs, and (5) no or acceptable expression on mature blood cells. Applying a 20-point scoring framework, 13 novel antigens emerged as the most promising candidates for CAR-T-cell therapy in AML: ADGRE2, SIGLEC-6, IL1RAP, MUC1, CCR1, CD155, CD70, LILRB4, GRP78, CD37, ITGB2, TIM-3 and mesothelin. We discuss the advantages and limitations of each target, along with strategies to mitigate associated risks. With no CAR-T-cell therapy currently approved for AML, this comprehensive review provides a prioritized antigen landscape and a framework to guide the rational design of next-generation CARs for this challenging malignancy.

DOI: https://doi.org/10.1038/s41408-026-01544-5
Am J Hematol. 2026 Jun 19.

ICC/WHO-Defined and NGS-Annotated Idiopathic Hypereosinophilia (iHES/iHE): Mutations, Clinical and Treatment Details, and Predictors of Survival.

Shraddha P Patel, Muhammad Yousuf, Rania Abdelaziz, Priyansh Faldu, Shivani P Udyawar, Aysel Kaplan Bayraktar, Abiola B Bolarinwa, Cinthya J Zepeda Mendoza, Kaaren K Reichard, David S Viswanatha, Rong He, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi.



Keywords:  clonal hematopoiesis of indeterminate potential (CHIP); hypereosinophilic syndrome (HES); mepolizumab

DOI:  https://doi.org/10.1002/ajh.70413
Acta Haematol. 2026 Jun 15. 1-20

Limited prognostic value of ELN classification and relevance of molecular ontogeny in acute myeloid leukemia post myeloproliferative neoplasms: a retrospective multicenter study.

Edmond Chiche, Caroline Fileni, Sarah Bonnet, Sarah Bertoli, Andrew T Kuykendall, Lauris Gastaud, Michael Loschi, Geoffroy Venton, Véronique De Mas, Eric Delabesse, Alice Marceau-Renaut, Claude Preudhomme, Frederic Courtier, Anne Murati, Berengere Dadone-Montaudie, David Sallman, Christian Récher, Norbert Vey, Thomas Cluzeau.

Acute myeloid leukemia (AML) post myeloproliferative neoplasm (MPN) have very poor prognosis and are often excluded from most clinical trials. We retrospectively collected data from 166 patients, including 156 with available treatment data and 83 with NGS data treated in France and US. 2022 ELN risk categories were favorable, intermediate and adverse in 3 (2%), 17 (13%) and 110 (85%), respectively. ORR was 57%, 20% and 25% in patients treated by intensive chemotherapy (IC), hypomethylating agents (HMA) and BSC (including low intensity treatments as hydroxyurea and low-dose cytarabine), respectively. 31 patients (22%) underwent allogeneic stem cell transplantation (ASCT). Median overall survival (OS) was 7.2 months without significant difference between IC and HMA (9,5 and 8,6 months, respectively). OS was significantly improved in patients allografted (6.7 vs 1.3 months, respectively, p<0.001). Even though 2017 and 2022 ELN risk categories were not prognostic for OS, we observed a prognostic impact on OS of Lindsley's classifier (p=0.014). In multivariate analysis, JAK2 mutation was associated with worse OS (p=0.037), whereas SRSF2 showed a trend toward adverse prognosis (p=0.057). Among functional groups, only spliceosome mutations predicted poor prognosis (p=0.015). In conclusion, we confirmed poor prognosis of AML post MPN. Classical prognostic classification was not validated in our cohort. We observed poor outcome using IC or HMA encouraging us to propose new clinical trials in this specific subgroup. Only ASCT was able to improve prognosis.

DOI: https://doi.org/10.1159/000552809
Cell Stem Cell. 2026 Jun 18. pii: S1934-5909(26)00199-2. [Epub ahead of print]

Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation.

James W Swann, Jun Hou Fung, Ziwei Chen, Oakley C Olson, Amélie Collins, Tenzin Lhakhang, Melissa A Proven, Ruiyuan Zhang, Raul Rabadan, Emmanuelle Passegué.

  Hematopoietic stem and progenitor cells (HSPCs) respond to infections, inflammation, and regenerative challenges using emergency myelopoiesis (EM) pathways to amplify myeloid cell production. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single-cell RNA sequencing (scRNA-seq) of murine HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies for enhancing myelopoiesis that act at different levels of the HSPC hierarchy and are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based EM activation module across diverse inflammatory challenges that is conserved in humans and informs outcomes in adult and pediatric acute myeloid leukemia. Our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts.

Keywords:  acute myeloid leukemia; differentiation; emergency myelopoiesis; hematopoietic stem and progenitor cell; inflammation; quantitative model; regeneration; topology

DOI:  https://doi.org/10.1016/j.stem.2026.05.007
Biomark Res. 2026 Jun 17. pii: 62. [Epub ahead of print]14(1):

NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS.

Nemo Ikonen, Tanja Ruokoranta, Salla Hyyppä, Ella Sinervuori, Juho J Miettinen, Joseph Saad, Markus Vähä-Koskela, Caroline A Heckman.

  Chromosome 7 abnormalities -7 and -7q define a high-risk subset of myelodysplastic syndromes (MDS) with poor prognosis. The NAMPT gene, located at 7q22.3, encodes a rate limiting enzyme (nicotinamide phosphoribosyl transferase) in the NAD+ salvage pathway. Several inhibitors of NAMPT have been developed, but their activity in MDS has not been previously described. In this study, we investigated if MDS myeloblasts are susceptible to NAMPT inhibition. We show that primary bone marrow cells from patients with -7/-7q MDS exhibit strong and select sensitivity. Bulk viability assays and single cell, multiparametric flow cytometry confirmed enhanced NAMPT inhibitor sensitivity across leukemic cell populations, especially CD34 + CD38+ blasts from -7/-7q MDS samples compared to non -7/-7q MDS and healthy donor bone marrow cells. The NAMPT inhibitor KPT-9274 combined with BCL2 inhibitor venetoclax was particularly effective at targeting MDS blasts compared to NAMPT inhibition alone. MDS samples with -7/-7q also showed significantly lower NAMPT expression compared to the non -7/-7q samples, indicative of haploinsufficient gene expression profile. In conclusion, these findings support NAMPT haploinsufficiency as a vulnerability and as biomarker for NAMPT inhibitor activity in -7/-7q MDS.

Keywords:  MDS; Monosomy 7; NAMPT

DOI:  https://doi.org/10.1186/s40364-026-00956-6
Leukemia. 2026 Jun 18.

Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study.

S Rinaldetti, M Chepeleva, A Hedblom, C Sticht, M Muciek, P Panayiotidis, J Richter, U Olsson-Strömberg, D Nowak, V Nowak, P Ljungman, N von Bubnoff, K Lotfi, L Stenke, T H Brümmendorf, H Hjorth-Hansen, T Gedde-Dahl, W Majeed, A Burchert, P V Nazarov, E Felde, I Tarnopolscaia, C Hoelting, A Fabarius, W-K Hofmann, F-X Mahon, S Saussele, M Pfirrmann.

The European Stop Kinase Inhibitors (EURO-SKI) trial was launched to investigate the discontinuation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML). The molecular mechanisms underlying sustained treatment-free remission (TFR) and loss of TFR, are still poorly understood. To address this, we performed whole transcriptome gene expression analyses coupled with NanoString nCounter-based absolute gene quantification. Gene expression was assessed in peripheral blood leukocytes from 240 CML patients on the final day of TKI intake (training sample: n = 122, validation sample: n = 118) as well as from 10 healthy controls. To identify TKI-specific mechanisms, transcriptomic data from an external dataset of 96 TKI-naïve CML patients was incorporated into our analyses. TFR patients showed an activation of GATA1, KLF1 and MYBL1 regulons characteristic for erythroid progenitor cells. TFR patients maintain persistent communication between innate (natural killer and dendritic cells) and adaptive immunity (e.g., CD8+, CD4+, and γδ T lymphocytes), mirroring patterns observed in healthy controls. This intercellular communication is disrupted in patients with loss of TFR. Furthermore, we identified an FLT3 threshold that distinguished two patient groups with significantly different probabilities of TFR loss. Leveraging mechanisms that reestablish or reinforce the communication between innate and adaptive immunity could be pivotal in achieving durable TFR.

DOI: https://doi.org/10.1038/s41375-026-03001-5
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2507773123

Mathematical modeling of JAK2V617F clonal expansion in a general population cohort.

Jordan Snyder, Morten Andersen, Johanne Gudmand-Høyer, Morten Kranker Larsen, Vibe Skov, Lasse Kjær, Christina Schjellerup Eickhardt-Dalbøge, Trine A Knudsen, Christina Ellervik, Hans C Hasselbalch, Johnny T Ottesen, Thomas Stiehl.

  The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers characterized by overproduction of one or more types of blood cells, which can lead to thrombosis and other complications. MPNs develop slowly and are driven by a relatively small set of mutations in the hematopoietic stem cells (HSCs). Their slow development (over the course of decades) affords a unique opportunity to study their onset, but until recently few data have been available from individuals not yet showing overt disease. Thanks to the ambitious Danish General Suburban Population Study conducted in suburban Zealand, Denmark, we have identified a ([Formula: see text]) cohort of individuals harboring the most common driver mutation in MPN (namely JAK2V617F) and have obtained follow-up measurements of their variant allele fraction (VAF) spanning over 10 y. We show that these data are consistent with a Moran model governing the competition between healthy and mutated HSCs, and estimate the selective advantage of the mutant clone for each individual. Notably, we find that for many individuals, the change in VAF over many years is statistically consistent with zero, or even negative, selective advantage. This is in contrast to prior studies that have focused on patients diagnosed with overt MPN disease, in whom the mutant cells are almost always found to outcompete the healthy cells. Our results have implications for our understanding of the very early phases of MPN disease, and may contribute to early detection and personalized prediction of disease progression.

Keywords:  early detection; mathematical modeling; myeloproliferative neoplasms

DOI:  https://doi.org/10.1073/pnas.2507773123
Oncogene. 2026 Jun 13.

Targeting mitochondrial TRIP13-AIF interaction suppresses myeloid leukemia progression and overcomes drug resistance.

Yao Zhu, Hongcai Liu, Fuqiang Wang, Minjie Li, Nana Wang, Shuyue Zhan, Wenjie Sun, Shengxi Li, Xun Wang, Lin Wang, Lianjun Zhang, Zhimin Gu.

Venetoclax-based therapies have revolutionized acute myeloid leukemia (AML) treatment, yet disease progression remains a challenge due to limited response and acquired drug resistance. Identifying molecular drivers of AML progression and resistance is essential for improving therapeutic outcomes. Genes normally silenced in normal tissues but aberrantly activated in cancers, such as Cancer-Testis (CT) genes, are promising targets for cancer diagnostics and therapy. Through a CRISPR screen focused on CT genes and cancer-associated genes exhibiting a CT-like expression profile (CT-like gene), we identified the ATPase TRIP13 as critical for AML progression while dispensable for normal hematopoiesis in genetic mouse models. Mechanistically, we discovered that TRIP13 localizes to mitochondria, where it interacts with apoptosis-inducing factor (AIF), a component of respiratory complex I. This interaction promotes leukemia progression and confers drug resistance by preventing AIF translocation to the nucleus, thereby reducing apoptotic priming and shifting energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) coupled with increased fatty acid oxidation (FAO). Genetic or pharmacological disruption of the TRIP13-AIF interaction suppressed OXPHOS, reduced leukemia cell viability, and overcame venetoclax resistance in vitro and in vivo. These findings uncover a novel mechanism by which AML cells exploit germline programs to sustain progression and resist therapy, positioning the TRIP13-AIF interaction as a promising therapeutic target for AML.

DOI: https://doi.org/10.1038/s41388-026-03852-3
Am J Hematol. 2026 Jun 17.

Systemic Mastocytosis in Adults: 2026 Update on Diagnosis, Risk Stratification and Management.

Animesh Pardanani.

OVERVIEW: Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extra-cutaneous organs.
DIAGNOSIS: The major criterion is the presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and the presence of activating KIT mutations.
RISK STRATIFICATION: Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), or mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients.
MANAGEMENT: Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological, and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.

DOI: https://doi.org/10.1002/ajh.70395
Nat Commun. 2026 Jun 20.

ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.

Jacklyn M Huhn, Liana Valin, Mary Basse, Judith Sokei, Nishanth Gabriel, Esteban Martinez, Joice S Kanefsky, Stephanie Stransky, Adrienne Dorrance, Ramiro Garzon, Daniela Di Marcantonio, Tomasz Skorski, Aaron R Goldman, Hsin-Yao Tang, Samuele Cortellazzi, Orsola di Martino, John Krais, Simone Sidoli, Francesca Ferraro, David L Wiest, Stephen M Sykes.

Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.

DOI: https://doi.org/10.1038/s41467-026-74324-1
Haematologica. 2026 Jun 18.

Dual CDK2 and CDK4/6 inhibition suppresses Rb/E2F signaling and enhances anti-leukemic activity in acute myeloid leukemia.

Ellen Weisberg, Basudev Chowdhury, Swati Garg, Taisei Akatsu, Wei Ni, Prafulla C Gokhale, Benjamin K Eschle, Sydney Grant, Martin Sattler, James A DeCaprio, Lukas Nöltner, Jacqueline Garcia, Kate Marinchev, Ilene Galinsky, Aritro Nath, Richard M Stone, James D Griffin.

The cyclin-dependent kinase 6 (CDK6) is a central regulator of cell cycle progression and an important contributor to the development of acute leukemia, particularly in poor prognosis subtypes. Preclinical studies have demonstrated activity of CDK6-targeting drugs in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), but clinical trials with CDK4/6 inhibitors as monotherapy were disappointing. In contrast, clinical efficacy was observed for the combination of the dual CDK4/6 inhibitor, palbociclib, with chemotherapy in pediatric acute leukemia and lymphoma patients. We sought to evaluate the potential of CDK6 inhibition to sensitize AML cells to both standard-of-care and novel targeted therapies. We found the CDK2- targeting drug, tegtociclib, to be particularly effective in potentiating the inhibitory effects of CDK4/6 inhibitors against acute leukemia cells. While similar strategies have been considered for solid tumors where CDK4/6 targeted agents may work as monotherapy, we have discovered a unique and novel approach to introduce this class of drugs to acute leukemias. Our results also demonstrate that synergy between these agents, as has been previously shown in breast cancer, is also observed in acute leukemia and correlates with suppression of the Rb/E2F axis and inhibition of cell cycle progression. The universality between the underlying mechanisms of synergy for CDK2 inhibitors combined with CDK4/6 inhibitors in breast cancer and AML warrants further evaluation in other malignancies characterized by dependencies on these CDK subtypes.

DOI: https://doi.org/10.3324/haematol.2026.300728
Blood Adv. 2026 Jun 18. pii: bloodadvances.2026020372. [Epub ahead of print]

Outcomes of Adolescents and Young Adults with AML Treated on Pediatric vs Adult Protocols.

Baher Krayem, Jeetayu Biswas, Andriy Derkach, Michael Rafizadeh, Jenna R Ciervo, Christopher A Famulare, Omar Abdel-Wahab, Neerav N Shukla, Tanya Trippett, Christopher Jon Forlenza, Kavitha Ramaswamy, Martin S Tallman, Mark B Geyer, Maria Luisa Sulis, Eytan M Stein.

Adolescents and young adults (AYA) with acute myeloid leukemia (AML) represent a biologically and clinically distinct population managed across pediatric and adult oncology services, with no established optimal treatment paradigm. In this single-center retrospective study, we analyzed 81 AYA patients aged 14-29 years with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between 2010 and 2025. Patients were stratified by treating service, European LeukemiaNet (ELN) 2022 risk category, and induction regimen. Pediatric patients received two cycles of cytarabine, daunorubicin, and etoposide (ADE)-based induction, while adult patients received one cycle of cytarabine plus daunorubicin (7+3) induction-three of whom required 7+3 reinduction-followed by risk-adapted consolidation including allogeneic hematopoietic stem cell transplantation. Composite complete response rates were similar between adult and pediatric cohorts (79% vs. 78%), as were rates of MRD negativity by multicolor flow cytometry among responders (63% vs. 55%). Despite comparable depth of response, five-year overall survival favored adult-service patients in both the full cohort (77.9% vs. 56.7%) and the ELN 2022 intermediate-adverse risk subgroup (62.7% vs. 47.9%), while relapse-free survival was nearly identical. On multivariable analysis, ELN 2022 risk retained independent prognostic significance, whereas treatment protocol did not. These findings demonstrate that pediatric-style and adult AML regimens achieve comparable remission depth in AYA patients. The survival advantage observed with adult protocols challenges the assumption that further cytotoxic intensification improves outcomes in this population.

DOI: https://doi.org/10.1182/bloodadvances.2026020372
Blood Neoplasia. 2026 Aug;3(3): 100243

Bone marrow immunosuppressive states associate with survival after guadecitabine and atezolizumab therapy in HMA-R/R MDS.

H Josh Jang, Guillermo Urrutia, Andreas Due Ørskov, Anh Van Nguyen, Hyeon Jin Kim, Seth A Nelson, Hyein Lee, Ryan S Burgos, Benjamin K Johnson, Marc Wegener, Katelyn Becker, Marie Adams, Rachael Sheridan, Zachary H Ramjan, Scott A Givan, Caitlin C Zebley, Benjamin A Youngblood, Jean-Pierre J Issa, Michael J Topper, Stephen B Baylin, Maria R Baer, Timothy J Triche, Casey L O'Connell, Kirsten Grønbæk, Peter A Jones.

Approximately half of patients with myelodysplastic syndromes (MDS) relapse or are refractory to hypomethylating agents (HMAs) and experience poor clinical outcomes. We previously reported improved survival in a phase 1/2 clinical trial combining the HMA guadecitabine with a programmed death-ligand 1 (PD-L1) inhibitor (atezolizumab) in HMA-relapsed or HMA-refractory (HMA-R/R) MDS, yet the biological features associated with durable responses to this combined epigenetic and immunotherapy approach remain unclear. Here, we performed integrated bulk and single-cell transcriptomic profiling of bone marrow samples from patients treated on this trial to identify molecular and cellular features associated with survival. Long-term survival was associated with the presence of immunosuppressive myeloid cells and primed dendritic cells at baseline, together with therapy-induced immune reinvigoration characterized by interferon pathway activation and expansion of effector lymphocytes. In contrast, short-term survival was associated with persistent senescence-associated inflammatory programs in CD34+ bone marrow cells and elevated expression of immunosuppressive immune checkpoint molecules. These findings suggest that chronic inflammatory and senescent microenvironmental states constrain effective immune activation despite combined epigenetic and immune checkpoint therapy. Here, we identify distinct bone marrow microenvironments associated with patient survival after combined epigenetic and immune checkpoint therapy and suggest candidate biomarkers to guide patient stratification in HMA-R/R MDS.

DOI: https://doi.org/10.1016/j.bneo.2026.100243
Nat Commun. 2026 Jun 19.

PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1.

Céline Philippe, Shoshana Burke, Arantxa Carrasco-Leon, Andrea Martisova, Pedro Casado, Eleni Maniati, Jimena Castorena, Pantelitsa Protopapa, Alyssa Fronk, Ru-Pin Alicia Chi, Rachel Boniface, Vinothini Rajeeve, Martin Dodel, Beatriz Galvão, Marc Aubry, Kaliya Svetlinova Georgieva, Doriana Di Bella, Brian N Papas, Taylor Floyd, Kendall Anderson, Martin Akerman, Jun Wang, Lovorka Stojic, Faraz Mardakheh, Marcos Morgan, Eric Chevet, Christian Touriol, Pedro R Cutillas, Kevin Rouault-Pierre.

The unfolded protein response (UPR) is a critical adaptive program triggered upon cellular stresses that profoundly reshapes the transcriptome and translatome. In the very first minutes of cellular stress, translation blockage, RNA decay and RNA granules formation prompt the synthesis of proteins essential to the stress response. Due to the dynamic nature of these processes, investigating translation upon stress has proven to be challenging; therefore, our understanding of these mechanisms and translatome rewiring upon stress remains limited. Here, we exploit O-Propargyl-puromycin (OPP) labelling of de novo peptides followed by LC-MS/MS to identify de novo proteins translated upon endoplasmic reticulum (ER) stress. Combined with transcriptomic analyses, our approach reveals that ER stress profoundly impacts the synthesis of core splicing factor proteins leading to a significant reshaping of the splicing landscape. We identify a signature of seven splicing events consistently occurring in mammalian cells exposed to ER stress. Using pharmacological, genetic, phosphoproteomic and sequencing approaches, we demonstrate that this specific signature is driven by PERK activation and is dependent on the axis CLK1/SRSF1. Our findings identify PERK/CLK1/SRSF1 -mediated splicing regulation as a new facet of ER stress, defining an ERi-splice signature spanning healthy and malignant tissues.

DOI: https://doi.org/10.1038/s41467-026-74397-y
Blood. 2026 Jun 15. pii: blood.2025031490. [Epub ahead of print]

FAP-1 loss impairs megakaryocyte demarcation membrane system and platelet function with myelofibrosis-like features.

Mu-Fan Chiu, Kun-Huei Yeh, Pei-Jer Chen, Wen-Chien Chou, Chung-Wu Lin, Koping Chang, Chien-Chin Lin, Shiou-Hwei Yeh.

Fas-associated phosphatase-1 (FAP-1), a nonreceptor protein tyrosine phosphatase, has been implicated in multiple signaling pathways, but its in vivo role remains unclear. Here, we show that FAP-1-deficient (FAP-1ΔP/ΔP) mice develop early megakaryocyte hyperplasia with defective platelet function and occasional hemorrhagic manifestations, accompanied by myelofibrosis-like features in aged animals. Bone marrow analysis revealed impaired demarcation membrane system (DMS) development with pre-DMS arrest in megakaryocytes, leading to defective proplatelet formation and impaired platelet function, with prolonged bleeding partly associated with reduced clot retraction. Mechanistically, FAP-1 deficiency induces sustained Src activation and cofilin inactivation, impairing perinuclear actin remodeling required for DMS expansion and resulting in pre-DMS arrest. With aging, approximately half of mice develop a symptomatic phenotype characterized by extramedullary hematopoiesis, hepatosplenomegaly, anemia, and thrombocytopenia; among these, most remain in a prefibrotic state, while a subset progresses to fibrosis-like changes. Bone marrow transplantation demonstrates that megakaryocyte abnormalities and fibrosis-associated changes are hematopoietic cell-intrinsic and partially transferable. Pharmacologic inhibition of Src with dasatinib attenuates these defects in FAP-1-deficient mice, supporting pathway specificity. In patients with primary myelofibrosis, reduced FAP-1 expression is associated with pre-DMS megakaryocyte accumulation, abnormal DMS and actin organization, and Src activation, supporting clinical relevance. Collectively, we identify a FAP-1-dependent mechanism governing Src-cofilin-mediated actin remodeling required for megakaryocyte maturation and platelet function, and suggest this pathway as a potential therapeutic target for platelet dysfunction, hemorrhagic complications, and fibrosis-associated disease.

DOI: https://doi.org/10.1182/blood.2025031490
iScience. 2026 Jun 19. 29(6): 116202

ALDH3A2-mediated fatty acid synthesis induces ferroptosis and AML drug resistance.

Yun Huang, Yu Zhao, Ping Yan, Zhiquan Long, Chuang Xia, Ling Jiang, Yujiao Zhang, Jiaying Cheng, Fang Liu, Quan Wu, Zhongzhen Zhou, Xuejie Jiang.

  Chemoresistance in acute myeloid leukemia (AML) is associated with a poor prognosis in patients. Ferroptosis is one of the mechanisms by which anthracycline exerts anti-leukemic effects, with drug-resistant AML cells exhibiting increased resistance to ferroptosis. Elevated expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) is correlated with poor prognosis in patients with AML. Patients with chemo-resistant AML exhibit higher levels of ALDH3A2, particularly the V subtype. ALDH3A2 degraded 4-hydroxynonenal and regulated the fatty acid proportion and content of AML cells, protecting AML cells against doxorubicin-induced ferroptosis. Moreover, overexpression of ALDH3A2 changes cell membrane fluidity and reduces drug uptake. Histone deacetylase 2 binds to the ALDH3A2 promoter and regulates its expression. The inhibition of ALDH3A2 or HDAC enhances chemotherapeutic efficacy in AML.

Keywords:  Cancer; Molecular network; Therapeutics

DOI:  https://doi.org/10.1016/j.isci.2026.116202
Hum Genomics. 2026 Jun 18.

Variant-specific SF3B1 mutations drive distinct splicing and mitochondrial dysfunction in myelodysplastic neoplasms.

Andrea Hruštincová, Iva Trsová, David Kundrát, Monika Beličková, Monika Kaisrlíková, Jitka Veselá, Zdeněk Krejčík, Alžběta Hlaváčková, Jiří Suttnar, Hana Štufková, Nikol Volfová, Hana Hansíková, Tatiana Aghová, Zuzana Zemanová, Anna Jonášová, Jaroslav Čermák, Markéta Šťastná Marková, Michaela Dostálová Merkerová.

   BACKGROUND: SF3B1 spliceosome mutations are among the most common genetic lesions in myelodysplastic neoplasms (MDS). The canonical hotspot K700E variant is generally associated with a favorable prognosis, whereas the impact of other recurrent variants is poorly defined. We investigated the clinical, transcriptomic, and functional consequences of distinct SF3B1 mutations in MDS patients and isogenic cell models.
METHODS: Clinical data from 121 SF3B1-mutated MDS patients were analyzed. RNA sequencing was performed on CD34⁺ patient bone marrow cells and CRISPR-engineered NALM-6 lines harboring individual SF3B1 variants. Comprehensive profiling of splicing, gene expression, and mitochondrial bioenergetic parameters was performed.
RESULTS: Compared with K700E, the K666 variant was associated with shorter progression-free survival, distinct splicing abnormalities, and a higher frequency of retained introns, showing partial overlap with the H662 variant. Mitochondria-related genes were frequently mis-spliced and differentially expressed in K666-variant cells. In isogenic models, reduced complex IV activity and marked OXPHOS impairment were observed, with the most pronounced effects seen in K666N. Overall, SF3B1 variants confer heterogeneous biological and clinical effects. The K666N variant, in particular, is associated with adverse prognosis and profound bioenergetic dysfunction.
CONCLUSIONS: These results support a refined view of SF3B1-mutated MDS as a biologically heterogeneous entity and suggest that variant-specific mitochondrial vulnerabilities may represent exploitable targets for precision-based therapeutic strategies.

Keywords:   SF3B1 ; Myelodysplastic neoplasms; RNA sequencing

DOI:  https://doi.org/10.1186/s40246-026-01000-2
Br J Haematol. 2026 Jun 17.

Outcome of treatment with trametinib in adults with histiocytic neoplasms in the United Kingdom.

Rodothea Amerikanou, Talha Munir, Kristian Bowles, Christopher McNamara, Nikesh Chavda, Elizabeth Price, Jagdish Adiyodi, Alasdair Coles, Philippa Kelsey, Jeffery Smith, Richard Adams, Hayder Hussein, Rui Zhao, Trung Nguyen, Matthew Collin, Satyen Gohil.

  Trametinib (MEK inhibitor) shows efficacy in refractory and high-risk adult histiocytic neoplasms. At a median follow-up of 21.4 months, the clinical response rate was 81% (30/37) and the radiological response was 68% (25/37) (n = 37).

Keywords:  Erdheim–Chester disease; Langerhans cell histiocytosis; Rosai–Dorfman disease; histiocytic sarcoma

DOI:  https://doi.org/10.1111/bjh.70617