bims-tremyl 2024-08-18 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2024–08–18
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Genetic Risk Stratification and Outcomes Among Treatment-Naive Patients With AML Treated With Venetoclax and Azacitidine.
Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations.
Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: a study of the ALWP of the EBMT.
IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.
A systematic review of venetoclax for the treatment of unfit AML patients in real-world: is all that glitters gold?
The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).
How to manage patients with germline DDX41 variants: Recommendations from the Nordic working group on germline predisposition for myeloid neoplasms.
A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis.
Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish.
Prototypical innate immune mechanism hijacked by leukemia-initiating mutant stem cells for selective advantage and immune evasion in Ptpn11-associated juvenile myelomonocytic leukemia.
Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.
Influence of genetic co-mutation on chemotherapeutic outcome in NPM1-mutated and FLT3-ITD wild-type AML patients.
Venetoclax-based non-intensive induction followed by allogenic stem-cell transplantation in elderly acute myeloid leukemia patients with adverse cytogenetics.
The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.
Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights.
Autophagy in cancer resistance: New combinatorial strategy for cancer therapy.
ROCK2 increases drug resistance in acute myeloid leukemia via metabolic reprogramming and MAPK/PI3K/AKT signaling.
Melphalan Dose in Combination with Fludarabine Affects GI Toxicity and GVHD after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Prognostic mutations identified by whole-exome sequencing and validation of the Molecular International Prognostic Scoring System in myelodysplastic syndromes after allogeneic haematopoietic stem cell transplantation.
Heterotypic interaction promotes asymmetric division of human hematopoietic progenitors.
Outcomes of adults with refractory or relapsed acute myeloid leukemia treated with azacitidine and venetoclax compared to other therapies: a multicenter retrospective study.
Molecular impact of mutations in RNA splicing factors in cancer.
The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia.
Association between JAK2V617F variable allele frequency and risk of thrombotic events in patients with myeloproliferative neoplasms.
Prognostic relevance of molecular measurable residual disease detection in AML with mutated CEBPA.
Histiocytosis of the orbit and its association with KRAS mutations.
Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.
Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids.
A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease.
The clinical implications of BCOR mutations in a large cohort of acute myeloid leukemia patients: a 5-year single-center retrospective study.
Mitochondrial complex I promotes kidney cancer metastasis.

Blood. 2024 Aug 12. pii: blood.2024024944. [Epub ahead of print]

Genetic Risk Stratification and Outcomes Among Treatment-Naive Patients With AML Treated With Venetoclax and Azacitidine.

Hartmut Döhner, Keith W Pratz, Courtney D DiNardo, Andrew H Wei, Brian A Jonas, Vinod Pullarkat, Michael J Thirman, Christan Récher, Andre C Schuh, Sunil Babu, Xiaotong Li, Grace Ku, Zihuan Liu, Yan Sun, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea.

European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to 2017 and 2022 ELN risk classifications. A bioinformatic algorithm derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on median overall survival (OS). 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. When classified by ELN 2017 or 2022 prognostic criteria, most patients had adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). While outcomes with venetoclax-azacitidine were improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine; the mutational status of TP53, FLT3-ITD, NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% CI, 20.2 to 32.7], 12.1 months [95% CI, 7.3 to 15.2], and 5.5 months [95% CI, 2.8 to 7.6], respectively). ELN prognostic classifiers do not provide clinically meaningful risk stratification of OS outcomes for patients with AML treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows classification of these patients into three risk groups with distinct differences in median OS.

DOI: https://doi.org/10.1182/blood.2024024944
Blood. 2024 Aug 12. pii: blood.2024025409. [Epub ahead of print]

Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations.

Hartmut Döhner, Courtney D DiNardo, Andrew H Wei, Bob Löwenberg, Frederick Appelbaum, Charles Craddock, Hervé Dombret, Benjamin L Ebert, Pierre Fenaux, Lucy A Godley, Robert P Hasserjian, Richard A Larson, Ross L Levine, Yasushi Miyazaki, Dietger Niederwieser, Gert J Ossenkoppele, Christoph Röllig, Jorge Sierra, Eytan M Stein, Martin S Tallman, Hwei-Fang Tien, Jianxiang Wang, Agnieszka Wierzbowska.

The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.

DOI: https://doi.org/10.1182/blood.2024025409
Bone Marrow Transplant. 2024 Aug 14.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: a study of the ALWP of the EBMT.

Razan Mohty, Abdul Hamid Bazarbachi, Myriam Labopin, Jordi Esteve, Nicolaus Kröger, Jan J Cornelissen, Didier Blaise, Gerard Socié, Sébastien Maury, Arnold Ganser, Tobias Gedde-Dahl, Peter von dem Borne, Jean Henri Bourhis, Claude Eric Bulabois, Ibrahim Yakoub-Agha, Caroline Pabst, Stéphanie Nguyen, Patrice Chevallier, Anne Huynh, Ali Bazarbachi, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1 and IDH2 mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with IDH1 mutation (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% CI 0.47-0.91), p = 0.011; HR = 0.73 (95% CI 0.56-0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48-0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34-0.7), p < 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95% CI 0.55-0.9), p = 0.004) and OS (HR = 0.74 (95% CI 0.56-0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes. In conclusion, our data suggest that IDH1 and IDH2 mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1.

DOI: https://doi.org/10.1038/s41409-024-02384-2
J Hematol Oncol. 2024 Aug 14. 17(1): 67

IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.

Yi Zhang, Miso Park, Lucy Y Ghoda, Dandan Zhao, Melissa Valerio, Ebtesam Nafie, Asaul Gonzalez, Kevin Ly, Bea Parcutela, Hyeran Choi, Xubo Gong, Fang Chen, Kaito Harada, Zhenhua Chen, Le Xuan Truong Nguyen, Flavia Pichiorri, Jianjun Chen, Joo Song, Stephen J Forman, Idoroenyi Amanam, Bin Zhang, Jie Jin, John C Williams, Guido Marcucci.

   BACKGROUND: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML.
METHODS: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples.
RESULTS: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002).
CONCLUSIONS: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Keywords:  Acute myeloid leukemia; IL1RAP; Immunotherapy; Leukemic stem cells; T cell engager

DOI:  https://doi.org/10.1186/s13045-024-01586-x
Ann Hematol. 2024 Aug 16.

A systematic review of venetoclax for the treatment of unfit AML patients in real-world: is all that glitters gold?

Antonio Solana-Altabella, Rebeca Rodríguez-Veiga, David Martínez-Cuadrón, Pau Montesinos.

  Acute myeloid leukemia (AML) is an aggressive hematological disease that mainly affects elderly patients. Following the randomized VIALE-A trial, current standard treatment in patients who are not candidates for intensive chemotherapy consists of the combination of venetoclax (VEN), a selective inhibitor of the anti-apoptotic protein BCL-2, with azacitidine (AZA) or decitabine (DEC). We performed a systematic review to critically assess the growing existing evidence regarding the effectiveness of the VEN-based combinations in unfit adult patients with newly diagnosed AML in the real-world setting. Following PRISMA guidelines, a systematic search of published manuscripts and conference abstracts (European Hematology Association and American Society of Hematology) was conducted (updated March 2024). Primary outcomes were composite complete remission (CRc) and median overall survival (mOS). A total of 73 studies fulfilled inclusion criteria, with a median age of 73 years old. The weighted mean mOS was 10.3 months among 7 138 patients, significantly lower than expected according to the VIALE-A trial (14.7 months), while the weighted mean CRc rate was 58.2% among 5 831 patients, slightly lower to that reported in the VIALE-A (66.4%). Early death rates at 30 and 60 days were 5% and 13%, respectively. The weighted mean percentage of subsequent allogeneic transplant was 15.4%. In conclusion, breakthrough mOS reported in the VIALE-A trial using VEN-AZA was not well reproduced in real world for unfit newly diagnosed AML patients, while CRc rates were more consistent. Strategies to optimize patient selection, dosing regimens, and supportive care are crucial to improve outcomes in real-world.

Keywords:  AML; Newly diagnosed; Real-world; Unfit; Venetoclax

DOI:  https://doi.org/10.1007/s00277-024-05891-w
Cancers (Basel). 2024 Jul 27. pii: 2675. [Epub ahead of print]16(15):

The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).

Sara Pierangeli, Serena Donnini, Valerio Ciaurro, Francesca Milano, Valeria Cardinali, Sofia Sciabolacci, Gaetano Cimino, Ilaria Gionfriddo, Roberta Ranieri, Sabrina Cipriani, Eleonora Padiglioni, Roberta Iacucci Ostini, Tiziana Zei, Antonio Pierini, Maria Paola Martelli.

  How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Keywords:  IDH1/2 mutation; acute myeloid leukemia; human HSPC modeling

DOI:  https://doi.org/10.3390/cancers16152675
Hemasphere. 2024 Aug;8(8): e145

How to manage patients with germline DDX41 variants: Recommendations from the Nordic working group on germline predisposition for myeloid neoplasms.

Panagiotis Baliakas, Bianca Tesi, Jörg Cammenga, Asbjørg Stray-Pedersen, Kirsi Jahnukainen, Mette Klarskov Andersen, Helena Ågerstam, Maria Creignou, Ingunn Dybedal, Klas Raaschou-Jensen, Kirsten Grønbæk, Outi Kilpivaara, Eva Hellström Lindberg, Ulla Wartiovaara-Kautto.

Increasing recognition of germline DDX41 variants in patients with hematological malignancies prompted us to provide DDX41-specific recommendations for diagnosis, surveillance, and treatment. Causative germline variants in the DDX41 predispose to the development of myeloid neoplasms (MNs), especially myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Almost 3%-5% of all patients with MDS or AML carry a pathogenic or likely pathogenic germline DDX41 variant, while half of them acquire a somatic second hit in the other allele. DDX41-associated MNs exhibit unique clinical characteristics compared to other hematological malignancies with germline predisposition: MNs occur mostly at advanced age and follow an indolent clinical course. Male carriers are more prone to develop MDS or AML than females. DDX41-associated MN is often hypoplastic, and the malignancy may be preceded by cytopenias.

DOI: https://doi.org/10.1002/hem3.145
Ann Hematol. 2024 Aug 15.

A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis.

Ghaith Abu-Zeinah, Albert Qin, Harinder Gill, Norio Komatsu, John Mascarenhas, Weichung Joe Shih, Oleh Zagrijtschuk, Toshiaki Sato, Kazuya Shimoda, Richard T Silver, Ruben Mesa.

  Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.

Keywords:  Disease-modifying; Early/lower risk PMF; Placebo controlled phase 3; Pre-fibrotic PMF; Primary myelofibrosis (PMF); Randomized; Ropeginterfeon alfa-2b

DOI:  https://doi.org/10.1007/s00277-024-05912-8
Leukemia. 2024 Aug 13.

Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish.

Sarada Ketharnathan, Sujata Pokharel, Sergey V Prykhozhij, Anna Cordeiro-Santanach, Kevin Ban, Serkan Dogan, Huy-Dung Hoang, Mira F Liebman, Elaine Leung, Tommy Alain, Irina Alecu, Steffany A L Bennett, Miroslava Čuperlović-Culf, Yigal Dror, Jason N Berman.

Mutations in the DNAJC21 gene were recently described in Shwachman-Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using the zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth, and defective protein synthesis. We show that cytopenia results from impaired hematopoietic differentiation, accumulation of DNA damage, and reduced cell proliferation. The introduction of a biallelic tp53 mutation in the dnajc21 mutants leads to the development of myelodysplastic neoplasia-like features defined by abnormal erythroid morphology and expansion of hematopoietic progenitors. Using transcriptomic and metabolomic analyses, we uncover a novel role for Dnajc21 in nucleotide metabolism. Exogenous nucleoside supplementation restores neutrophil counts, revealing an association between nucleotide imbalance and neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology.

DOI: https://doi.org/10.1038/s41375-024-02367-8
Res Sq. 2024 Aug 02. pii: rs.3.rs-4450642. [Epub ahead of print]

Prototypical innate immune mechanism hijacked by leukemia-initiating mutant stem cells for selective advantage and immune evasion in Ptpn11-associated juvenile myelomonocytic leukemia.

Cheng-Kui Qu, Hong Zheng, Peng Zhao, Zhenya Tan, Wen-Mei Yu, Juwita Werner, Elliot Stieglitz, Chris Porter, Shanmuganathan Chandrakasan, Daniel Wechsler, Simon Mendez-Ferrer.

Juvenile myelomonocytic leukemia (JMML), a clonal hematologic malignancy, originates from mutated hematopoietic stem cells (HSCs). The mechanism sustaining the persistence of mutant stem cells, leading to leukemia development, remains elusive. In this study, we conducted comprehensive examination of gene expression profiles, transcriptional factor regulons, and cell compositions/interactions throughout various stages of tumor cell development in Ptpn11 mutation-associated JMML. Our analyses revealed that leukemia-initiating Ptpn11 E76K/+ mutant stem cells exhibited de novo activation of the myeloid transcriptional program and aberrant developmental trajectories. These mutant stem cells displayed significantly elevated expression of innate immunity-associated anti-microbial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8 . Biological experiments confirmed that S100a9/S100a8 conferred a selective advantage to the leukemia-initiating cells through autocrine effects and facilitated immune evasion by recruiting and promoting immune suppressive myeloid-derived suppressor cells (MDSCs) in the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impeded leukemia development from Ptpn11 E76K/+ mutant stem cells. These findings collectively suggest that JMML tumor-initiating cells exploit evolutionarily conserved innate immune and inflammatory mechanisms to establish clonal dominance.

DOI: https://doi.org/10.21203/rs.3.rs-4450642/v1
J Oncol Pharm Pract. 2024 Aug 16. 10781552241276547

Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.

Dat Ngo, Jose Tinajero, Jianying Zhang, Anthony Stein, Guido Marcucci, Amandeep Salhotra, Vinod Pullarkat, Karamjeet S Sandhu, Brian J Ball, Hoda Pourhassan, Paul Koller.

   INTRODUCTION: Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors.
METHODS: We retrospectively reviewed 40 patients between 2017-2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML.
RESULTS: Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups.
CONCLUSION: Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.

Keywords:  Acute myeloid leukemia; FLT3 inhibitors; midostaurin

DOI:  https://doi.org/10.1177/10781552241276547
Cancer Med. 2024 Aug;13(15): e70102

Influence of genetic co-mutation on chemotherapeutic outcome in NPM1-mutated and FLT3-ITD wild-type AML patients.

Quan Wu, Yujiao Zhang, Baoyi Yuan, Yun Huang, Ling Jiang, Fang Liu, Ping Yan, Jiaying Cheng, Zhiquan Long, Xuejie Jiang.

   BACKGROUND: Nucleophosmin 1 (NPM1) gene-mutated acute myeloid leukemia (NPM1mut AML) is classified as a subtype with a favorable prognosis. However, some patients fail to achieve a complete remission or relapse after intensified chemotherapy. Genetic abnormalities in concomitant mutations contribute to heterogeneous prognosis of NPM1mut AML patients.
METHODS: In this study, 91 NPM1-mutated and FLT3-ITD wild-type (NPM1mut/FLT3-ITDwt) AML patients with intermediate-risk karyotype were enrolled to analyze the impact of common genetic co-mutations on chemotherapeutic outcome.
RESULTS: Our data revealed that TET1/2 (52/91, 57.1%) was the most prevalent co-mutation in NPM1mut AML patients, followed by IDH1/2 (36/91, 39.6%), DNMT3A (35/91, 38.5%), myelodysplastic syndrome related genes (MDS-related genes) (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 genes) (35/91, 38.5%), FLT3-TKD (27/91, 29.7%) and GATA2 (13/91, 14.3%) mutations. Patients with TET1/2mut exhibited significantly worse relapse-free survival (RFS) (median, 28.7 vs. not reached (NR) months; p = 0.0382) compared to patients with TET1/2wt, while no significant difference was observed in overall survival (OS) (median, NR vs. NR; p = 0.3035). GATA2mut subtype was associated with inferior OS (median, 28 vs. NR months; p < 0.0010) and RFS (median, 24 vs. NR months; p = 0.0224) compared to GATA2wt. By multivariate analysis, GATA2mut and MDS-related genesmut were independently associated with worse survival.
CONCLUSION: Mutations in TET1/2, GATA2 and MDS-related genes were found to significantly influence the chemotherapeutic outcome of patients with NPM1mut AML. The findings of our study have significant clinical implications for identifying patients who have an adverse response to frontline chemotherapy and provide a novel reference for further prognostic stratification of NPM1mut/FLT3-ITDwt AML patients.

Keywords:  acute myeloid leukemia; chemotherapy; molecular genetics; survival

DOI:  https://doi.org/10.1002/cam4.70102
Eur J Haematol. 2024 Aug 11.

Venetoclax-based non-intensive induction followed by allogenic stem-cell transplantation in elderly acute myeloid leukemia patients with adverse cytogenetics.

Amel Soua, Julia Gilhodes, Alexandre Iat, Yosr Hicheri, Colombe Saillard, Camille Rouzaud, Evelyne D'Incan, Jérôme Rey, Bilal Mohty, Aude Charbonnier, Antoine Ittel, Anne-Sophie Alary, Véronique Gelsi-Boyer, Anne Murati, Anne-Catherine Lhoumeau, Raynier Devillier, Jean-Marie Boher, Marie-Joelle Mozziconacci, Norbert Vey, Marie-Anne Hospital, Sylvain Garciaz.

   INTRODUCTION: Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients.
MATERIALS AND METHODS: We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019.
RESULTS: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06).
CONCLUSION: VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

Keywords:  TP53; acute myeloid leukemia; adverse cytogenetics; venetoclax

DOI:  https://doi.org/10.1111/ejh.14290
Nature. 2024 Aug 14.

The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

Petri Pölönen, Danika Di Giacomo, Anna Eames Seffernick, Abdelrahman Elsayed, Shunsuke Kimura, Francesca Benini, Lindsey E Montefiori, Brent L Wood, Jason Xu, Changya Chen, Zhongshan Cheng, Haley Newman, Jason Myers, Ilaria Iacobucci, Elizabeth Li, Jonathan Sussman, Dale Hedges, Yawei Hui, Caroline Diorio, Lahari Uppuluri, David Frank, Yiping Fan, Yunchao Chang, Soheil Meshinchi, Rhonda Ries, Rawan Shraim, Alexander Li, Kathrin M Bernt, Meenakshi Devidas, Stuart S Winter, Kimberly P Dunsmore, Hiroto Inaba, William L Carroll, Nilsa C Ramirez, Aaron H Phillips, Richard W Kriwacki, Jun J Yang, Tiffaney L Vincent, Yaqi Zhao, Pankaj S Ghate, Jian Wang, Colleen Reilly, Xin Zhou, Mathijs A Sanders, Junko Takita, Motohiro Kato, Nao Takasugi, Bill H Chang, Richard D Press, Mignon Loh, Evadnie Rampersaud, Elizabeth Raetz, Stephen P Hunger, Kai Tan, Ti-Cheng Chang, Gang Wu, Stanley B Pounds, Charles G Mullighan, David T Teachey.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

DOI: https://doi.org/10.1038/s41586-024-07807-0
Cancers (Basel). 2024 Jul 24. pii: 2634. [Epub ahead of print]16(15):

Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights.

Shalmali Pendse, Dirk Loeffler.

  Clonal hematopoiesis (CH), the relative expansion of mutant clones, is derived from hematopoietic stem cells (HSCs) with acquired somatic or cytogenetic alterations that improve cellular fitness. Individuals with CH have a higher risk for hematological and non-hematological diseases, such as cardiovascular disease, and have an overall higher mortality rate. Originally thought to be restricted to a small fraction of elderly people, recent advances in single-cell sequencing and bioinformatics have revealed that CH with multiple expanded mutant clones is universal in the elderly population. Just a few years ago, phylogenetic reconstruction across the human lifespan and novel sensitive sequencing techniques showed that CH can start earlier in life, decades before it was thought possible. These studies also suggest that environmental factors acting through aberrant inflammation might be a common theme promoting clonal expansion and disease progression. However, numerous aspects of this phenomenon remain to be elucidated and the precise mechanisms, context-specific drivers, and pathways of clonal expansion remain to be established. Here, we review our current understanding of the cellular mechanisms driving CH and specifically focus on how pro-inflammatory factors affect normal and mutant HSC fates to promote clonal selection.

Keywords:  Asxl1; CHIP; Dnmt3a; Tet2; clonal evolution; clonal hematopoiesis; clonal selection; hematopoietic stem cells; inflammation; self-renewal

DOI:  https://doi.org/10.3390/cancers16152634
Leukemia. 2024 Aug 15.

Autophagy in cancer resistance: New combinatorial strategy for cancer therapy.

Eloïne Bestion, Régis Costello, Soraya Mezouar, Philippe Halfon.

DOI: https://doi.org/10.1038/s41375-024-02342-3
Int Immunopharmacol. 2024 Aug 09. pii: S1567-5769(24)01418-8. [Epub ahead of print]140 112897

ROCK2 increases drug resistance in acute myeloid leukemia via metabolic reprogramming and MAPK/PI3K/AKT signaling.

Muxia Yan, Xin Luo, Hong Han, Jiachun Qiu, Qian Ye, Li Zhang, Yiqian Wang.

  Rho-associated coiled-coil kinase 2 (ROCK2) is classified as a member of the serine/threonine protein kinase family and has been identified as a key driver of the development of various forms of cancer. The cause of ROCK2's impact on acute myeloid leukemia (AML) is still unknown. We found that ROCK2 expression was higher in AML patients, leading to lower complete response rates and worse overall survival. Additionally, ROCK2 expression was elevated in the doxorubicin-resistant leukemia cell line HL-60/ADM when compared to their individual parent cells. Moreover, the suppression or inhibition of ROCK2 leads to enhanced drug sensitivity in both AML cell lines and primary AML specimens, along with a notable decrease in downstream signaling pathways. Furthermore, the suppression of ROCK2 caused disruption of cellular energy production pathways by directly affecting the functionality of proteins within the mitochondrial electron transport chain. Finally, we discovered that TRIM26, a specific E3 ligase, is capable of ubiquitylating ROCK2, and the upregulation of TRIM26 within HL-60/ADM cells resulted in heightened sensitivity to the drug and reduced resistance. Thus, our study presents a new strategy for overcoming drug resistance in AML through targeting ROCK2/AKT/MAPK signaling pathway.

Keywords:  Acute myeloid leukemia; Drug resistance; Metabolic reprogramming; ROCK2

DOI:  https://doi.org/10.1016/j.intimp.2024.112897
Transplant Cell Ther. 2024 Aug 13. pii: S2666-6367(24)00588-8. [Epub ahead of print]

Melphalan Dose in Combination with Fludarabine Affects GI Toxicity and GVHD after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Omar Albanyan, Hany Elmariah, Denise Kalos, Jongphil Kim, Rawan Faramand, David Sallman, Asmita Mishra, Kendra Sweet, Lia Perez, Jose Ochoa-Bayona, Michael Nieder, Rami Komrokji, Jeffery Lancet, Hugo Fernandez, Taiga Nishihori, Joseph Pidala, Claudio Anasetti, Nelli Bejanyan.

  Fludarabine (Flu) and melphalan (Mel) reduced-intensity conditioning is frequently used for allogenic hematopoietic cell transplant (allo-HCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, there is limited evidence on the impact of Mel dosing on toxicities and clinical outcomes of allo-HCT. We retrospectively compared 8/8 HLA matched donor allo-HCT outcomes of 345 patients with AML or MDS receiving total Mel dose of 100 mg/m2 (Mel-100, n=62) versus 140 mg/m2 (Mel-140, n=283) in combination with Flu. Median age at allo-HCT was 66 years and median follow-up was 36.5 months. For Mel-100 versus Mel-140 groups, any grade gastrointestinal toxicity rates were 40.3% vs. 67.8% (p<0.001), day 100 grade II-IV acute graft-versus-host disease (GVHD) rates were 21.0% vs. 43.1% (p=0.001) and 2-year chronic GVHD rates were 17.4% vs. 27.1% (p=0.033). In multivariable analysis, Mel-140 resulted in higher risks of gastrointestinal toxicity (HR=1.83, p=0.013), grade II-IV acute GVHD (HR=2.35, p=0.003), and moderate/severe chronic GVHD (HR=3.13, p=0.007). Total Mel dose had no independent impact on oral mucositis, non-relapse mortality, relapse, relapse-free survival, and overall survival. While independent validation of our observation is warranted, our findings support using Mel-100 in combination with Flu to minimize allo-HCT toxicities and morbidities related to GVHD.

Keywords:  Allogenic stem cell transplant; Melphalan and fludarabine RIC; Reduced intensity conditioning regimen; graft versus host disease; transplant toxicity

DOI:  https://doi.org/10.1016/j.jtct.2024.08.007
Br J Haematol. 2024 Aug 13.

Prognostic mutations identified by whole-exome sequencing and validation of the Molecular International Prognostic Scoring System in myelodysplastic syndromes after allogeneic haematopoietic stem cell transplantation.

Hong Wang, Xueqian Li, Jiaqian Qi, Hong Liu, Tiantian Chu, Xiaoyan Xu, Huiying Qiu, Chengcheng Fu, Xiaowen Tang, Changgeng Ruan, Depei Wu, Yue Han.

  In this study, we used the whole-exome sequencing (WES) approach to obtain genomic profiles from 92 marrow samples of myelodysplastic syndrome (MDS) patients before haematopoietic stem cell transplantation. We identified 129 mutations in 45 driver genes. Fifty-five patients (59.8%) carried at least 1 driver mutation. The splicing factor U2AF1 was the most frequently mutated in the cohort (21 cases, 23%), followed by BCOR (9 cases, 10%), ASXL1 (8 cases, 9%), TET2 (6 cases, 7%), NPM1 (5 cases, 5%), RUNX1 (5 cases, 5%), and SETBP1 (5 cases, 5%). WES also identified 49 possible oncogenic variants in six genes (PIEZO1, LOXHD1, MYH13, DNAH5, DPH1, and USH2A) that were associated with overall survival (OS) or relapse-free survival (RFS) in MDS after transplantation. Multivariate analysis showed mutations in DNAH5 and USH2A to be independent risk factors for OS. Mutations in DNAH5 and LOXHD1 were risk factors for worse RFS. The Molecular International Prognostic Scoring System retained its independent prognostic significance for RFS after multivariate analysis.

Keywords:  Molecular International Prognostic Scoring System; haematopoietic stem cell transplantation; myelodysplastic syndrome; prognosis; whole‐exome sequencing

DOI:  https://doi.org/10.1111/bjh.19707
Development. 2024 Aug 13. pii: dev.203088. [Epub ahead of print]

Heterotypic interaction promotes asymmetric division of human hematopoietic progenitors.

Adrian Candelas, Benoit Vianay, Matthieu Gelin, Lionel Faivre, Jerome Larghero, Laurent Blanchoin, Manuel Théry, Stéphane Brunet.

  Hematopoietic Stem and Progenitor Cells (HSPCs) give rise to all cell types of the hematopoietic system through various processes including asymmetric divisions. However, the contribution of stromal cells of the hematopoietic niches in the control of HSPC asymmetric divisions remains unknown. Using polyacrylamide microwells as minimalist niches, we show that specific heterotypic interaction with osteoblast and endothelial cell promote asymmetric division of human HSPC. Upon interaction, HSPCs polarize in interphase with the centrosome, the Golgi apparatus, and lysosomes positioned close to the site of contact. Subsequently, during mitosis, HSPCs orient their spindle perpendicular to the plane of contact. This division mode gives rise to siblings with unequal amounts of lysosomes and of CD34 differentiation marker. Such asymmetric inheritance generates heterogeneity in the progeny, which is likely to contribute to the plasticity of the early steps of hematopoiesis.

Keywords:  Asymmetric division; Hematopoiesis; Heterotypic interaction; Microfabrication; Niches; Stem cells

DOI:  https://doi.org/10.1242/dev.203088
Leuk Lymphoma. 2024 Aug 11. 1-9

Outcomes of adults with refractory or relapsed acute myeloid leukemia treated with azacitidine and venetoclax compared to other therapies: a multicenter retrospective study.

Andrée-Anne Pelland, Xavier Deschênes-Simard, Xavier Savard, Philippe Giguère, David Spillane, Frédéric Barabé, Vincent Laroche, Michaël Munger, Geneviève Gallagher, Nicolas Marcoux, Guy Cantin, Maxime Chénard-Poirier, Robert Delage, Marc Lalancette, Olivier Veilleux, Sarit E Assouline, Christopher Lemieux.

  This study reports characteristics and outcomes of adults who received Azacitidine-Venetoclax (AZA-VEN) compared to other salvage therapies (NO-AZA-VEN) as first salvage therapy for acute myeloid leukemia (AML). The clinical data of 81 patients with a diagnosis of relapsed or refractory AML were analyzed. The ORR was comparable for both groups (55% vs 57%, p = 0.852). Median OS (6.8 vs 11.2 months, p = 0.053) and median RFS (6.9 vs 11.2 months, p = 0.488) showed a trend in favor of the NO-AZA-VEN group. OS was significantly longer with NO-AZA-VEN for ELN 2022 risk category sub-group, patients under 60 years old, primary AML and for patients who underwent allo-hematopoietic stem cell transplant after salvage therapy. There was no statistical difference in complications of treatment such as febrile neutropenia, intensive care unit stay, septic shock and total parenteral nutrition. Those results do not support the preferential use of AZA-VEN over other regimens in R/R acute myeloid leukemia.

Keywords:  Acute myeloid leukemia; azacitidine-venetoclax; chemotherapy regimens; relapsed/refractory

DOI:  https://doi.org/10.1080/10428194.2024.2390574
Mol Cell. 2024 Aug 05. pii: S1097-2765(24)00617-8. [Epub ahead of print]

Molecular impact of mutations in RNA splicing factors in cancer.

Qian Zhang, Yuxi Ai, Omar Abdel-Wahab.

  Somatic mutations in genes encoding components of the RNA splicing machinery occur frequently in multiple forms of cancer. The most frequently mutated RNA splicing factors in cancer impact intronic branch site and 3' splice site recognition. These include mutations in the core RNA splicing factor SF3B1 as well as mutations in the U2AF1/2 heterodimeric complex, which recruits the SF3b complex to the 3' splice site. Additionally, mutations in splicing regulatory proteins SRSF2 and RBM10 are frequent in cancer, and there has been a recent suggestion that variant forms of small nuclear RNAs (snRNAs) may contribute to splicing dysregulation in cancer. Here, we describe molecular mechanisms by which mutations in these factors alter splice site recognition and how studies of this process have yielded new insights into cancer pathogenesis and the molecular regulation of splicing. We also discuss data linking mutant RNA splicing factors to RNA metabolism beyond splicing.

Keywords:  RBM10; RNA; SF3B1; SRSF2; SUGP1; U2AF1; ZRSR2; introns; spliceosome; splicing

DOI:  https://doi.org/10.1016/j.molcel.2024.07.019
Blood Transfus. 2024 Aug 06.

The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia.

Huiru Wang, Shanglong Feng, Yanliang Zhu, Yafeng Zhang, Ziwei Zhou, Zhigang Nian, Xueqin Lu, Peng Peng, Shu Wu, Li Zhou.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by high heterogeneity, poor long-term survival, and a propensity for relapse. Exceptional efficacy in treating recurrent or refractory B-lymphoid malignancies has been demonstrated by Chimeric antigen receptor T cells (CAR-T cells). Given the therapeutic potential of targeting both CD33 and C-type lectin-like molecule-1 (CLL1) in AML, the development of a dual-targeting CD33-CLL1 CAR-T cells assumes significant importance.
MATERIALS AND METHODS: The expressions of CD33 and CLL-1 antigens in peripheral blood cells and bone marrow cells from AML patients was assessed. Subsequently, a Chimeric Antigen Receptor (CAR) incorporating a dual-specific single-chain variable fragment targeting CLL1 and CD33 (CD33-CLL1-CAR-T) was engineered. The anti-tumor efficacy and potential side effects of CD33-CLL1-CAR-T cells were comprehensively investigated in both in vitro and in vivo settings.
RESULTS: The constructed tandem CD33-CLL1 CAR-T exhibited potent cytotoxicity against leukemia cell lines and human primary AML cells in vitro. Co-cultivation of AML blasts with CD33-CLL1-CAR-T cells resulted in effective proliferation and the secretion of substantial quantities of GM-CSF and IFN-γ. Importantly, the impact of CD33-CLL1-CAR-T cells on normal hematopoietic stem cells was minimal, ensuring safety in vivo mouse models. Notably, significant anti-leukemic activity was observed in the mouse model, with CD33-CLL1-CAR-T cells leading to tumor eradication and prolonged survival.
DISCUSSION: The tandem CD33-CLL1 CAR-T cells not only efficiently eliminated AML blasts but also exhibited low cytotoxicity toward normal hematopoietic stem cells (HSCs). These findings underscore the potential clinical applicability of the tandem CD33-CLL1 CAR-T cells as an effective and safe treatment strategy for AML, representing a noteworthy advancement in the field of CAR-T cells therapy.

DOI: https://doi.org/10.2450/BloodTransfus.786
Ir J Med Sci. 2024 Aug 14.

Association between JAK2V617F variable allele frequency and risk of thrombotic events in patients with myeloproliferative neoplasms.

Ryan Brown, Joanna Jasiakiewicz, Victoria Greer, Andrew Hindley, Katie McDowell, Eadaoin Devlin, Kathryn Clarke, Frances Buckley, Clare Crean, Julie McGimpsey, Robert J G Cuthbert, Nick Cunningham, Claire Arnold, Damian Finnegan, Gary Benson, Mary Frances McMullin, Mark A Catherwood.

   BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of chronic disorders of the bone marrow characterised by the overproduction of clonal myeloid stem cells. The most common driver mutation found in MPNs is a point mutation on exon 14 of the JAK2 gene, JAK2V617F. Various studies have suggested that measuring the variable allele frequency (VAF) of JAK2V617F may provide useful insight regarding diagnosis, treatment, risks and outcomes in MPN patients. In particular, JAK2V617F has been associated with increased risk of thrombotic events, a leading cause of mortality in MPNs.
AIMS: The aim of this study was to determine if JAK2V617F VAF was associated with clinical outcomes in patients with MPN.
METHODS: JAK2V617F VAF was determined by quantitative PCR (qPCR) in a cohort of 159 newly diagnosed MPN patients, and the association of JAK2V617F VAF and risk of thrombosis was examined in this cohort.
RESULTS: We observed a significantly higher JAK2V617F VAF in PV and PMF versus ET. A significant association was observed between JAK2V617F VAF and risk of thrombotic events. When patients were stratified by thrombotic events prior to and post diagnosis, an association with JAK2V617F VAF was only observed with post diagnosis thrombotic events. Of note, these associations were not observed when looking at each MPN subtype in isolation.
CONCLUSIONS: We have shown that a higher JAK2V617F VAF is associated with thrombotic events post MPN diagnosis. JAK2V617F VAF may therefore provide a valuable prognostic indicator for risk of thrombosis in MPNs.

Keywords:   JAK2 ; Myeloproliferative neoplasm; Thrombosis; Variable allele frequency

DOI:  https://doi.org/10.1007/s11845-024-03776-5
Hemasphere. 2024 Aug;8(8): e141

Prognostic relevance of molecular measurable residual disease detection in AML with mutated CEBPA.

Christian M Vonk, Emma L Boertjes, Francois G Kavelaars, Melissa Rijken, Jolinda M L Konijnenburg, Roxanne E Cromwell, Bob Löwenberg, Tim Grob, Peter J M Valk.

DOI: https://doi.org/10.1002/hem3.141
Blood Adv. 2024 Aug 12. pii: bloodadvances.2024014031. [Epub ahead of print]

Histiocytosis of the orbit and its association with KRAS mutations.

Jasmine H Francis, Rebecca F Silverman, Julia Canestraro, Dana Bossert, David Della Rocca, Vaios Hatzoglou, David H Abramson, Eli L Diamond.

DOI: https://doi.org/10.1182/bloodadvances.2024014031
Commun Biol. 2024 Aug 09. 7(1): 967

Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.

Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel.

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular identity, mPTP conductance is restored. In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies oxidative phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo. Additionally, differentiating pluripotent stem cells (PSCs) acquire greater organization of mitochondrial cristae and hematopoietic activity following knockdown of the CypD gene, Ppif. Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate.

DOI: https://doi.org/10.1038/s42003-024-06671-y
Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2409262121

Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Jing Tian, Joseph L Goldstein, Shili Li, Marc M Schumacher, Michael S Brown.

  Insig-1 and Insig-2 are endoplasmic reticulum (ER) proteins that inhibit lipid synthesis by blocking transport of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2) from ER to Golgi. In the Golgi, SREBPs are processed proteolytically to release their transcription-activating domains, which enhance the synthesis of fatty acids, triglycerides, and cholesterol. Heretofore, the two Insigs have redundant functions, and there is no rationale for two isoforms. The current data identify a specific function for Insig-2. We show that eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, inhibits fatty acid synthesis in human fibroblasts and rat hepatocytes by activating adenylate cyclase, which induces protein kinase A (PKA) to phosphorylate serine-106 in Insig-2. Phosphorylated Insig-2 inhibits the proteolytic processing of SREBP-1, thereby blocking fatty acid synthesis. Phosphorylated Insig-2 does not block the processing of SREBP-2, which activates cholesterol synthesis. Insig-1 lacks serine-106 and is not phosphorylated at this site. EPA inhibition of SREBP-1 processing was reduced by the replacement of serine-106 in Insig-2 with alanine or by treatment with KT5720, a PKA inhibitor. Inhibition did not occur in mutant human fibroblasts that possess Insig-1 but lack Insig-2. These data provide an Insig-2-specific mechanism for the long-known inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Keywords:  SREBP-1; cyclic AMP; fatty acid synthesis; mammalian cells; phosphorylated Insig-2

DOI:  https://doi.org/10.1073/pnas.2409262121
J Clin Oncol. 2024 Aug 16. JCO2400205

A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease.

Vijaya Raj Bhatt, Valerie K Shostrom, Hannah K Choe, Betty K Hamilton, Krishna Gundabolu, Lori J Maness, Virender Kumar, Ram I Mahato, Lynette M Smith, Taiga Nishihori, Stephanie J Lee.

PURPOSE: Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD.
PATIENTS AND METHODS: In a single-arm multicenter phase II trial (N = 47), adults with sclerotic cGVHD refractory to corticosteroids and ≥one additional line of systemic therapy for cGVHD received ruxolitinib for ≥six months (ClinicalTrials.gov identifier: NCT03616184). The primary end point was complete or partial response (PR) in skin and/or joint defined according to the 2014 National Institute of Health cGVHD Consensus Criteria.
RESULTS: Following the use of ruxolitinib for a median of 11 months, PR in skin and/or joints was noted in 49% (95% CI, 34 to 64) at 6 months, with 45% having joint and fascia response and 19% having skin response. The duration of skin/joint response was 77% (95% CI, 48 to 91) at 12 months. Overall cGVHD PR was noted in 47% (95% CI, 32 to 61). Improvement in Lee Symptom Scale summary and skin subscale scores was noted in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI, 10.0 to 34.1), nonrelapse mortality (NRM) of 2.2% (95% CI, 0.17 to 10.3), and no recurrent malignancy, failure-free survival (FFS) was 77.1% (95% CI, 61.3 to 87.0) at 12 months. Ruxolitinib was overall well tolerated with no new safety signals.
CONCLUSION: The use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, improvement in patient-reported outcomes, low NRM, and high FFS in patients with refractory sclerotic cGVHD. Ruxolitinib offers an effective treatment option for refractory sclerotic cGVHD.

DOI: https://doi.org/10.1200/JCO.24.00205
Leuk Lymphoma. 2024 Aug 10. 1-10

The clinical implications of BCOR mutations in a large cohort of acute myeloid leukemia patients: a 5-year single-center retrospective study.

Deyuan Hu, Kai Shen, YuSha Guo, Xie Bing Bao, Ningzheng Dong, Suning Chen.

  To elucidate the effect of BCOR mutation (BCORmut) on clinical outcomes, we included a total of 899 consecutive AML patients in a single-center during July 2016 to December 2021. Fifty cases (5.6%) had BCOR mutations, which co-occurred with mutations of RUNX1, DNMT3A, IDH2, BCORL1, STAG2, SF3B1 and U2AF1, but were exclusive with KIT and CEBPA mutations. BCORmut was also found to be exclusive with t(8;21)(q22;q22.1) AML in all patients and MLL rearrangements in the European Leukemia Net (ELN) adverse group. In those receiving intensive chemotherapy regimens, BCORmut was associated with lower complete remission (CR) rates and worse prognosis. Subgroup analysis showed that BCORmut mainly conferred a poor prognosis in the intermediate and adverse groups of the ELN2017 risk. These results suggest that BCOR mutation is an independent prognostic parameter in AML, implying BCOR mutation as a novel marker for chemorefractory disease and inferior prognosis.

Keywords:  AML; BCOR mutations; SF3B1 mutations; allo-HSCT; prognosis

DOI:  https://doi.org/10.1080/10428194.2024.2387730
Nature. 2024 Aug 14.

Mitochondrial complex I promotes kidney cancer metastasis.

Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

DOI: https://doi.org/10.1038/s41586-024-07812-3