bims-tremyl 2023-09-17 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023–09–17
34 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors.
Classification, risk stratification and response assessment in myelodysplastic syndromes/neoplasms (MDS): A state-of-the-art report on behalf of the International Consortium for MDS (icMDS).
Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.
AML with CEBPA mutations: A comparison of ICC and WHO-HAEM5 criteria in patients with 20% or more blasts.
Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients.
Spliceosome mutations are associated with clinical response in a phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia.
Clinical Correlates of Venetoclax-based Combination Sensitivities to Augment Acute Myeloid Leukemia Therapy.
Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy.
Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.
Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.
Cytidine deaminase status as a marker of response to azacytidine treatment in MDS and AML patients.
Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment.
Ppm1d truncating mutations promote the development of genotoxic stress-induced AML.
FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.
Infection risk associated with clonal hematopoiesis of indeterminate potential is partly mediated by hematologic cancer transformation in the UK Biobank.
Prognostic value of European Leukemia Net 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia.
Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib.
Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response.
Chronic inflammation promotes cancer progression in murine models.
Germline DDX41 mutant predisposition syndromes: Slow driver states to hematological malignancies.
A Deeply Quiescent Subset of CML LSC Depend on FAO Yet Avoid Deleterious ROS by Suppressing Mitochondrial Complex I.
Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia.
Lisi V, Blanchard È, Vladovsky M, et al. Unified gene expression signature of novel NPM1 exon 5 mutations in acute myeloid leukemia. Blood Adv. 2022;6(17):5160-5164.
Double trouble: IRAK1/4 inhibitors in AML/MDS.
Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia.
SOD1 is a synthetic lethal target in PPM1D -mutant leukemia cells.
Epitope Editing Prevents Off-Tumor Toxicity of CAR T-cell Therapy in AML.
Prospective analysis to determine barriers to allogeneic hematopoietic cell transplantation in patients with acute leukemia.
The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.
CD82 expression marks the endothelium to hematopoietic transition at the onset of blood specification in human.
Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.
Getting an aMPLe grasp on hematopoiesis.
Persistence of ex vivo expanded tumour and pathogen specific T-cells after allogeneic stem cell transplant for myeloid malignancies (the INTACT study).
Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome.

Blood Cancer J. 2023 Sep 11. 13(1): 142

Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors.

Nicholas J Short, Daniel Nguyen, Farhad Ravandi.

FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable for intensive chemotherapy due to age and/or comorbidities, and this population represents a particular unmet need. For these older patients who are unfit for intensive approaches, azacitidine + venetoclax is a new standard of care and is used by many clinicians irrespective of FLT3 mutation status. However, FLT3-ITD mutations confer resistance to venetoclax and are a well-established mechanism of relapse to lower-intensity venetoclax-based regimens, leading to short durations of remission and poor survival. Preclinical and clinical data suggest synergy between FLT3 inhibitors and venetoclax, providing rationale for their combination. Novel strategies to safely incorporate FLT3 inhibitors into the standard hypomethylating agent + venetoclax backbone are now being explored in this older, less fit population with newly diagnosed FLT3-mutated AML, with encouraging early results. Herein, we discuss the frontline use of FLT3 inhibitors in older adults with FLT3-mutated AML, including the potential role of FLT3 inhibitors in combination with intensive chemotherapy and as part of novel, lower-intensity doublet and triplet regimens in this older population.

DOI: https://doi.org/10.1038/s41408-023-00911-w
Blood Rev. 2023 Aug 19. pii: S0268-960X(23)00089-9. [Epub ahead of print] 101128

Classification, risk stratification and response assessment in myelodysplastic syndromes/neoplasms (MDS): A state-of-the-art report on behalf of the International Consortium for MDS (icMDS).

Maximilian Stahl, Jan Philipp Bewersdorf, Zhuoer Xie, Matteo Giovanni Della Porta, Rami Komrokji, Mina L Xu, Omar Abdel-Wahab, Justin Taylor, David P Steensma, Daniel T Starczynowski, Mikkael A Sekeres, Guillermo Sanz, David A Sallman, Gail J Roboz, Uwe Platzbecker, Mrinal M Patnaik, Eric Padron, Olatoyosi Odenike, Stephen D Nimer, Aziz Nazha, Ravi Majeti, Sanam Loghavi, Richard F Little, Alan F List, Tae Kon Kim, Christopher S Hourigan, Robert P Hasserjian, Stephanie Halene, Elizabeth A Griffiths, Steven D Gore, Peter Greenberg, Maria E Figueroa, Pierre Fenaux, Fabio Efficace, Amy E DeZern, Naval G Daver, Jane E Churpek, Hetty E Carraway, Rena Buckstein, Andrew M Brunner, Jacqueline Boultwood, Uma Borate, Rafael Bejar, John M Bennett, Andrew H Wei, Valeria Santini, Michael R Savona, Amer M Zeidan.

  The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes.

Keywords:  Diagnostic criteria; IPSS-M; MDS; Myelodysplastic syndrome; Novel therapies; Risk classification

DOI:  https://doi.org/10.1016/j.blre.2023.101128
J Clin Oncol. 2023 Sep 13. JCO2202604

Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.

Naval G Daver, Paresh Vyas, Suman Kambhampati, Monzr M Al Malki, Richard A Larson, Adam S Asch, Gabriel Mannis, Wanxing Chai-Ho, Tiffany N Tanaka, Terrence J Bradley, Deepa Jeyakumar, Eunice S Wang, Kendra Sweet, Hagop M Kantarjian, Guillermo Garcia-Manero, Rami Komrokji, Guan Xing, Giridharan Ramsingh, Camille Renard, Joshua F Zeidner, David A Sallman.

PURPOSE: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479).
PATIENTS AND METHODS: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR).
RESULTS: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively.
CONCLUSION: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.

DOI: https://doi.org/10.1200/JCO.22.02604
Leuk Res. 2023 Aug 29. pii: S0145-2126(23)00641-0. [Epub ahead of print]134 107376

AML with CEBPA mutations: A comparison of ICC and WHO-HAEM5 criteria in patients with 20% or more blasts.

Davidson Zhao, Qianghua Zhou, Mojgan Zarif, Entsar Eladl, Cuihong Wei, Eshetu G Atenafu, Andre Schuh, Anne Tierens, Yu Wing Tony Yeung, Mark D Minden, Hong Chang.

  AML with CEBPA mutation and AML with in-frame bZIP CEBPA mutations define favorable-risk disease entities in the proposed 5th edition of the World Health Organization Classification (WHO-HAEM5) and the International Consensus Classification (ICC), respectively. However, the impact of these new classifications on clinical practice remains unclear. We sought to assess the differences between the ICC and WHO-HAEM5 for AML with CEBPA mutation. 741 AML patients were retrospectively analyzed. Cox proportional-hazard regression was used to identify factors predictive of outcome. A validation cohort from the UK-NCRI clinical trials was used to confirm our findings. 81 (11%) AML patients had CEBPA mutations. 39 (48%) patients met WHO-HAEM5 criteria for AML with CEBPA mutation, among which 30 (77%) had biallelic CEBPA mutations and 9 (23%) had a single bZIP mutation. Among the 39 patients who met WHO-HAEM5 criteria, 25 (64%) also met ICC criteria. Compared to patients only meeting WHO-HAEM5 criteria, patients with in-frame bZIP CEBPA mutations (ie. meeting both WHO-HAEM5 and ICC criteria) were younger, had higher bone marrow blast percentages and CEBPA mutation burden, infrequently harboured 2022 ELN high-risk genetic features and co-mutations in other genes, and had superior outcomes. The associations in clinicopathological features and outcomes between the CEBPA-mutated groups were validated in the UK-NCRI cohort. Our study indicates that in-frame bZIP CEBPA mutations are the critical molecular aberrations associated with favorable outcomes in AML patients treated with curative intent chemotherapy. Compared to WHO-HAEM5, the ICC identifies a more homogenous group of CEBPA-mutated AML patients with favorable outcomes.

Keywords:  AML; CEBPA; ICC; Risk classification; WHO-HAEM5

DOI:  https://doi.org/10.1016/j.leukres.2023.107376
Br J Haematol. 2023 Sep 14.

Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients.

Ahmad Nanaa, Rong He, James M Foran, Talha Badar, Naseema Gangat, Animesh Pardanani, William J Hogan, Mark R Litzow, Mrinal Patnaik, Aref Al-Kali, Hassan B Alkhateeb.

  Venetoclax (VEN) is an FDA-approved selective inhibitor of B-cell leukaemia/lymphoma-2 (BCL-2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high-risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.

Keywords:   DDX41 ; hypomethylating agents; response; treatment; venetoclax

DOI:  https://doi.org/10.1111/bjh.19105
Ann Hematol. 2023 Sep 13.

Spliceosome mutations are associated with clinical response in a phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia.

Peter J P Croucher, Maya Ridinger, Pamela S Becker, Tara L Lin, Sandra L Silberman, Eunice S Wang, Amer M Zeidan.

  PLK1 is overexpressed in acute myeloid leukemia (AML). A phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. A total of 44 R/R AML patients were treated with ONV + DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (n = 32). A 10-gene expression signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Twenty percent of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi), and 32% exhibited a ≥50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset. By applying the signature to the BeatAML cohort (n = 399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.

Keywords:  AML; Biomarker; Hypomethylating agents; Onvansertib; PLK1; Splicing

DOI:  https://doi.org/10.1007/s00277-023-05442-9
Blood Cancer Discov. 2023 Sep 12.

Clinical Correlates of Venetoclax-based Combination Sensitivities to Augment Acute Myeloid Leukemia Therapy.

Christopher A Eide, Stephen E Kurtz, Andy Kaempf, Nicola Long, Sunil Kumar Joshi, Tamilla Nechiporuk, Ariane Huang, Charles A Dibb, Akosha Taylor, Daniel Bottomly, Shannon K McWeeney, Jessica Minnier, Curtis A Lachowiez, Jennifer N Saultz, Ronan T Swords, Anupriya Agarwal, Bill H Chang, Brian J Druker, Jeffrey W Tyner.

The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared to venetoclax+azacytidine (Ven+Azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven+Azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state-independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses.

DOI: https://doi.org/10.1158/2643-3230.BCD-23-0014
bioRxiv. 2023 Sep 01. pii: 2023.08.30.555598. [Epub ahead of print]

Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy.

Samantha Kaonis, Jenny L Smith, Neerja Katiyar, Morgan Merrill, Tiffany Hyelkma, Stephanie Namciu, Quy Le, Ekaterina Babaeva, Takashi Ishida, Shelli M Morris, Emily Girard, Suzanne Furuyama, Rhonda Ries, Irwin Bernstein, Soheil Meshinchi, Steven Henikoff, Michael Meers, Brandon Hadland, Jay F Sarthy.

Oncogenic fusions involving transcription factors are present in the majority of pediatric leukemias; however, the context-specific mechanisms they employ to drive cancer remain poorly understood. CBFA2T3-GLIS2 (C/G) fusions occur in treatment-refractory acute myeloid leukemias and are restricted to young children. To understand how the C/G fusion drives oncogenesis we applied CUT&RUN chromatin profiling to an umbilical cord blood/endothelial cell (EC) co-culture model of C/G AML that recapitulates the biology of this malignancy. We find C/G fusion binding is mediated by its zinc finger domains. Integration of fusion binding sites in C/G- transduced cells with Polycomb Repressive Complex 2 (PRC2) sites in control cord blood cells identifies MYCN, ZFPM1, ZBTB16 and LMO2 as direct C/G targets. Transcriptomic analysis of a large pediatric AML cohort shows that these genes are upregulated in C/G patient samples. Single cell RNA-sequencing of umbilical cord blood identifies a population of megakaryocyte precursors that already express many of these genes despite lacking the fusion. By integrating CUT&RUN data with CRISPR dependency screens we identify BRG1/SMARCA4 as a vulnerability in C/G AML. BRG1 profiling in C/G patient-derived cell lines shows that the CBFA2T3 locus is a binding site, and treatment with clinically-available BRG1 inhibitors reduces fusion levels and downstream C/G targets including N-MYC, resulting in C/G leukemia cell death and extending survival in a murine xenograft model.

DOI: https://doi.org/10.1101/2023.08.30.555598
Mol Cancer Res. 2023 Sep 12.

Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.

Diyu Hou, Xiaoming Zheng, Danni Cai, Ruolan You, Jingru Liu, Xiaoting Wang, Xinai Liao, Maoqing Tan, Liyan Lin, Jin Wang, Shuxia Zhang, Huifang Huang.

Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum interleukin-6 (IL-6) levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL-6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL-6 facilitates the development of chemoresistance in AML cells. IL-6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL-6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL-6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used anti-leukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL-6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL-6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL-6 may have therapeutic implications in overcoming IL-6-mediated chemoresistance in AML. Implications: IL-6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL-6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0382
Am J Hematol. 2023 Sep 13.

Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.

Parth C Patel, Somedeb Ball, Akriti G Jain, Chen Wang, Mohammad O Hussaini, Luis E Aguirre, Onyee Chan, Seongseok Yun, Andrew Kuykendall, Eric Padron, Kendra Sweet, Jeffrey E Lancet, Rami S Komrokji, David A Sallman.

A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.

DOI: https://doi.org/10.1002/ajh.27092
Br J Haematol. 2023 Sep 10.

Cytidine deaminase status as a marker of response to azacytidine treatment in MDS and AML patients.

Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Guillaume Sicard, Florian Correard, Laure Farnault, L'Houcine Ouafik, Geoffroy Venton, Raphaëlle Fanciullino.

  Azacitidine (Aza) is a mainstay of treatment for patients with acute myeloid leukaemia (AML) ineligible for induction chemotherapy and other high-risk myelodysplastic syndromes (MDS). Only half of patients respond, and almost all will eventually relapse. There are no predictive markers of response to Aza. Aza is detoxified in the liver by cytidine deaminase (CDA). Here, we investigated the association between CDA phenotype, toxicity and efficacy of Aza in real-world adult patients. Median overall survival (OS) was 15 months and 13 months in AML and high-risk MDS patients respectively. In addition, our data suggest that delaying Aza treatment was not associated with lack of efficacy and should not be considered a signal to switch to an alternative treatment. Half of the patients had deficient CDA activity (i.e. <2 UA/mg), with a lower proportion of deficient patients in MDS patients (34%) compared to AML patients (67%). In MDS patients, CDA deficiency correlated with longer landmark OS (14 vs. 8 months; p = 0.03), but not in AML patients. Taken together, our data suggest that CDA is an independent covariate and may therefore be a marker for predicting clinical outcome in MDS patients treated with Aza.

Keywords:  AML; MDS; azacitidine; cytidine deaminase; efficacy/toxicity

DOI:  https://doi.org/10.1111/bjh.19096
Cell Rep. 2023 Sep 12. pii: S2211-1247(23)01109-9. [Epub ahead of print] 113098

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment.

Tomohiro Yabushita, Takumi Chinen, Atsuya Nishiyama, Shuhei Asada, Ruka Shimura, Tomoya Isobe, Keita Yamamoto, Naru Sato, Yutaka Enomoto, Yosuke Tanaka, Tomofusa Fukuyama, Hitoshi Satoh, Keiko Kato, Kaori Saitoh, Takamasa Ishikawa, Tomoyoshi Soga, Yasuhito Nannya, Tatsuo Fukagawa, Makoto Nakanishi, Daiju Kitagawa, Toshio Kitamura, Susumu Goyama.

  Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

Keywords:  ATR; CHK1; CP: Cancer; DNA hypomethylating agent; DNA methylation; DNMT1; HMA; cholesterol; decitabine; mitosis; mitotic catastrophe

DOI:  https://doi.org/10.1016/j.celrep.2023.113098
Leukemia. 2023 Sep 14.

Ppm1d truncating mutations promote the development of genotoxic stress-induced AML.

Monika Burocziova, Petr Danek, Anna Oravetzova, Zuzana Chalupova, Meritxell Alberich-Jorda, Libor Macurek.

Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of PPM1D lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.

DOI: https://doi.org/10.1038/s41375-023-02030-8
Leukemia. 2023 Sep 09.

FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.

Kasidy K Dobish, Karli J Wittorf, Samantha A Swenson, Dalton C Bean, Catherine M Gavile, Nicholas T Woods, Gargi Ghosal, R Katherine Hyde, Shannon M Buckley.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing FBXO21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibition of tumor progression, and sensitization to chemotherapy agents. Additionally, knockdown of FBXO21 leads to up-regulation of cytokine signaling pathways. Through a mass spectrometry-based proteomic analysis of FBXO21 in AML, we identified that FBXO21 ubiquitylates p85α, a regulatory subunit of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in decreased PI3K signaling, dimerization of free p85α and ERK activation. These findings reveal the ubiquitin E3 ligase, FBXO21, plays a critical role in regulating AML pathogenesis, specifically through alterations in PI3K via regulation of p85α protein stability.

DOI: https://doi.org/10.1038/s41375-023-02020-w
Leukemia. 2023 Sep 09.

Infection risk associated with clonal hematopoiesis of indeterminate potential is partly mediated by hematologic cancer transformation in the UK Biobank.

Caitlyn Vlasschaert, Elvis Akwo, Cassianne Robinson-Cohen, Elina K Cook, Matthew B Lanktree, Michael J Rauh, Alexander G Bick.

DOI: https://doi.org/10.1038/s41375-023-02023-7
Haematologica. 2023 Sep 14.

Prognostic value of European Leukemia Net 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia.

Silvia Park, Tong Yoon Kim, Byung-Sik Cho, Daehun Kwag, Jong-Mi Lee, MyungShin Kim, Yonggoo Kim, Jamin Koo, Anjali Raman, Tae Kon Kim, Hee-Je Kim.

This study aimed to validate the new European Leukemia Net (ELN) 2022 criteria for genetic risk stratification in older adults with acute myeloid leukemia (AML) and to determine the most likely set of clusters of similar cytogenetic and mutation properties correlated with survival outcomes in three treatment groups: intensive chemotherapy (IC), hypomethylating agents (HMAs) alone, and HMAs plus venetoclax (HMA/VEN). The study included 279 patients (≥60 years) who received IC (n=131), HMA (n=76), and HMA/VEN (n=72) between July 2017 and October 2021. No significant differences were observed in survival among the groups according to ELN 2022 risk stratification. Unsupervised hierarchical clustering analysis identified nine genomic clusters (C1-9) with varying survival outcomes depending on treatment type. For example, C4 (predominant for core binding factor-AML) displayed a favorable prognosis in the IC group, but not in the HMA or HMA/VEN group. The HMA/VEN group had better outcomes than the HMA group in many clusters (C1, 2, 3, and 5); however, the addition of VEN to HMA or IC did not improve the survival outcomes compared with those of HMA alone in C7 and C9 [predominant for -5, del(5q), -7, -17/abn(17p), complex karyotypes, and mutated TP53 ]. The study highlights the limitations of ELN genetic risk stratification in older adults with AML. It emphasizes the need for a more comprehensive approach that considers co-occurring somatic mutations to guide treatment selection in older adults with AML potentially.

DOI: https://doi.org/10.3324/haematol.2023.283606
Blood Cancer J. 2023 Sep 11. 13(1): 143

Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib.

Chung H Kok, Verity A Saunders, Phuong Dang, Naranie Shanmuganathan, Deborah White, Susan Branford, David Yeung, Timothy P Hughes.

Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.

DOI: https://doi.org/10.1038/s41408-023-00917-4
Blood. 2023 Sep 12. pii: blood.2023022147. [Epub ahead of print]

Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response.

Stephanie N Hurwitz, Seul K Jung, Danielle R Kobulsky, Hossein Fazelinia, Lynn A Spruce, Empar Baltasar-Pérez, Nathalie Groen, Clementina Mesaros, Peter Kurre.

Hematopoietic stem and progenitor cell (HSPC) transplantation serves as a curative therapy for many benign and malignant hematopoietic disorders, and as a platform for gene therapy. However, growing needs for ex vivo manipulation of HSPC graft products are limited by barriers in maintaining critical self-renewal and quiescence properties. The role of sphingolipid metabolism in safeguarding these essential cellular properties has been recently recognized, but not yet widely explored. Here we demonstrate that pharmacologic and genetic inhibition of neutral sphingomyelinase-2 (nSMase2) leads to sustained improvements in long-term competitive transplantation efficiency after ex vivo culture. Mechanistically, nSMase2 blockade activates a canonical integrated stress response (ISR) and promotes metabolic quiescence in human and murine HSPCs. These adaptations result in part from disruption in sphingolipid metabolism that impairs the release of nSMase2-dependent extracellular vesicles (EVs). The aggregate findings link EV trafficking and the ISR as a regulatory dyad guarding HSPC homeostasis and long-term fitness. Translationally, transient nSMase2 inhibition enables ex vivo graft manipulation with enhanced HSPC potency.

DOI: https://doi.org/10.1182/blood.2023022147
Exp Hematol. 2023 Sep 12. pii: S0301-472X(23)01702-2. [Epub ahead of print]

Chronic inflammation promotes cancer progression in murine models.

Monika Burocziova, Srdjan Grusanovic, Karolina Vanickova, Sladjana Kosanovic, Meritxell Alberich-Jorda.

Acute myeloid leukemia (AML) is a malignant neoplasia of the hematopoietic system characterized by the accumulation of immature and non-functional leukemic blasts in the bone marrow and peripheral tissues. Mechanistically, the development of AML is explained by the "two-hit" theory, based on the accumulation of driver mutations that will cooperate to induce transformation. However, a significant percentage of AML patients exhibit only one driver mutation, and thus, how leukemic transformation occurs in these cases is unclear. Accumulating evidence suggests that non-genetic factors, such as chronic inflammation, might influence AML development, and accordingly, clinical data reported that patients with chronic inflammatory disorders have an increased risk of developing hematological malignancies. Here, using a mouse model of chronic inflammation, we demonstrate that systemic elevated levels of cytokines and chemokines, and hyper-activation of the Jak/Stat3 signaling pathway, might substitute "second hit" mutations and accelerate tumorigenesis. Altogether, our data highlights chronic inflammation as an additional factor in the development of AML, providing additional understanding of the mechanisms of transformation, and opening new venues for the treatment of this disease.

DOI: https://doi.org/10.1016/j.exphem.2023.09.002
Am J Hematol. 2023 Sep 13.

Germline DDX41 mutant predisposition syndromes: Slow driver states to hematological malignancies.

Timothy M Chlon, Mrinal M Patnaik.

DOI: https://doi.org/10.1002/ajh.27091
Curr Mol Pharmacol. 2023 Sep 06.

A Deeply Quiescent Subset of CML LSC Depend on FAO Yet Avoid Deleterious ROS by Suppressing Mitochondrial Complex I.

Nyam-Osor Chimge, Min-Hsuan Chen, Cu Nguyen, Yuqi Zhao, Xiwei Wu, Paulina Garcia Gonzalez, Heather Ogana, Samantha Hurwitz, Jia-Ling Teo, Xiaolong Chen, Juan Du, Victor Jin, Yong-Mi Kim, Masaya Ono, Rafael J Argüello, Michael Kahn.

   BACKGROUND AND OBJECTIVE: Disease relapse and therapy resistance remain serious impediments to treating cancer. Leukemia stem cells (LSC) are therapy resistant and the cause of relapse. A state of deep quiescence appears to enable cancer stem cells (CSC) to acquire new somatic mutations essential for disease progression and therapy resistance. Both normal hematopoietic stem cells (HSC) and LSC share many common features, thereby complicating the safe elimination of LSC. A recent study demonstrated that long lived normal oocytes exist without mitochondrial complex I (MC-1), expressing it in a developmentally regulated fashion, thereby mitigating their vulnerability to ROS. Quiescent CSC rely on mitochondrial FAO, without complex I expression, thereby avoiding the generation of damaging ROS, similar to long lived normal human stem cells. A deeper understanding of the biology of therapy resistance is important for the development of optimal strategies to attain complete leukemia cures.
METHODS: Here, using scRNA-sequencing and ATAC-seq on primary chronic myelogenous leukemia (CML) patient samples, combined with bioinformatics analyses, we further examine the heterogeneity of a previously characterized in vitro imatinib-selected CD34-CD38- CML LSC population. We utilized a series of functional analyses, including single-cell metabolomic and Seahorse analyses, to validate the existence of the deepest quiescent leukemia initiators (LI) subset.
RESULTS: Current study revealed heterogeneity of therapy resistant LSC in CML patients and their existence of two functionally distinct states. The most deeply quiescent LI suppress the expression of MC-1, yet are highly dependent on fatty acid oxidation (FAO) for their metabolic requirements and ATAC-seq demonstrated increased chromatin accessibility in this population, all consistent with an extremely primitive, quiescent stemness transcriptional signature. Importantly, the specific CREB binding protein (CBP)/β-catenin antagonist ICG-001 initiates the differentiation of LSC, including LI, decreases chromatin accessibility with differentiation and increasing expression of MC-1, CD34, CD38 and BCR-ABL1, thereby re-sensitizing them to imatinib.
CONCLUSION: We investigated the biological aspects related to LSC heterogeneity in CML patients and demonstrated the ability of specific small molecule CBP/β-catenin antagonists to safely eliminate deeply quiescent therapy resistant CSC. These observations may represent an attractive generalizable therapeutic strategy that could help develop better protocols to eradicate the quiescent LSC population.

Keywords:  CBP; CML; ICG-00; ICG-00CML; LI; LSC; MC-1; metabolism

DOI:  https://doi.org/10.2174/1874467217666230906092236
Cancer Cell Int. 2023 Sep 15. 23(1): 202

Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia.

Hayden L Bell, Helen J Blair, Mankaran Singh, Anthony V Moorman, Olaf Heidenreich, Frederik W van Delft, John Lunec, Julie A E Irving.

   BACKGROUND: Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated.
METHODS: Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively.
RESULTS: Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL.
CONCLUSIONS: Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.

Keywords:  Cell cycle checkpoints; High-risk; Inhibitors; Leukemia; Relapse; Translational; WEE1

DOI:  https://doi.org/10.1186/s12935-023-03057-8
Blood Adv. 2023 Sep 26. 7(18): 5314

Lisi V, Blanchard È, Vladovsky M, et al. Unified gene expression signature of novel NPM1 exon 5 mutations in acute myeloid leukemia. Blood Adv. 2022;6(17):5160-5164.

DOI: https://doi.org/10.1182/bloodadvances.2023011160
Blood. 2023 Sep 14. 142(11): 945-946

Double trouble: IRAK1/4 inhibitors in AML/MDS.

Hannah J Uckelmann, Jan-Henning Klusmann.

DOI: https://doi.org/10.1182/blood.2023020812
Clin Epigenetics. 2023 Sep 13. 15(1): 150

Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia.

Sam Humphries, Danielle R Bond, Zacary P Germon, Simon Keely, Anoop K Enjeti, Matthew D Dun, Heather J Lee.

   BACKGROUND: Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of DNA methylation is an important epigenetic driver of AML, where the hypoxic bone marrow microenvironment can help facilitate leukaemogenesis. Thus, interactions between epigenetic regulation and hypoxia signalling will have important implications for AML development and treatment.
MAIN BODY: This review summarises the importance of DNA methylation and the hypoxic bone marrow microenvironment in the development, progression, and treatment of AML. Here, we focus on the role hypoxia plays on signalling and the subsequent regulation of DNA methylation. Hypoxia is likely to influence DNA methylation through altered metabolic pathways, transcriptional control of epigenetic regulators, and direct effects on the enzymatic activity of epigenetic modifiers. DNA methylation may also prevent activation of hypoxia-responsive genes, demonstrating bidirectional crosstalk between epigenetic regulation and the hypoxic microenvironment. Finally, we consider the clinical implications of these interactions, suggesting that reduced cell cycling within the hypoxic bone marrow may decrease the efficacy of hypomethylating agents.
CONCLUSION: Hypoxia is likely to influence AML progression through complex interactions with DNA methylation, where the therapeutic efficacy of hypomethylating agents may be limited within the hypoxic bone marrow. To achieve optimal outcomes for AML patients, future studies should therefore consider co-treatments that can promote cycling of AML cells within the bone marrow or encourage their dissociation from the bone marrow.

Keywords:  Acute myeloid leukaemia; DNA methylation; Epigenetics; Hypoxia; Reactive oxygen species; Treatment outcomes

DOI:  https://doi.org/10.1186/s13148-023-01566-x
bioRxiv. 2023 Sep 01. pii: 2023.08.31.555634. [Epub ahead of print]

SOD1 is a synthetic lethal target in PPM1D -mutant leukemia cells.

Linda Zhang, Joanne I Hsu, Etienne D Braekeleer, Chun-Wei Chen, Tajhal D Patel, Hidetaka Urya, Anna G Guzman, Alejandra G Martell, Sarah M Waldvogel, Ayala Tovy, Elsa Callen, Rebecca Murdaugh, Rosemary Richard, Sandra Jansen, Lisenka Vissers, Bert B A de Vries, Andre Nussenzweig, Shixia Huang, Cristian Coarfa, Jamie N Anastas, Koichi Takahashi, George Vassiliou, Margaret A Goodell.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D -mutant cells. Moreover, we observed marked genomic instability in mutant cells, which is exacerbated upon inhibition of SOD1. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress and DNA damage in PPM1D -mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D -mutant cancers.

DOI: https://doi.org/10.1101/2023.08.31.555634
Cancer Discov. 2023 Sep 15. OF1

Epitope Editing Prevents Off-Tumor Toxicity of CAR T-cell Therapy in AML.

Epitope editing of hematopoietic stem and progenitor cells (HSPC) improves CAR T-cell efficacy in AML.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-145
Am J Hematol. 2023 Sep 09.

Prospective analysis to determine barriers to allogeneic hematopoietic cell transplantation in patients with acute leukemia.

Karthik Nath, Jasme Lee, Theresa A Elko, Lauren Levy, Elaina Preston, Sean M Devlin, Doris M Ponce, Richard J Lin, Brian C Shaffer, Christina Cho, Ioannis Politikos, Ann A Jakubowski, Jae H Park, Raajit Rampal, Miguel-Angel Perales, Martin S Tallman, Juliet N Barker, Ellin Berman, Roni Tamari, Eytan Stein, Sergio A Giralt, Boglarka Gyurkocza.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with acute leukemia. Despite this, studies have shown that only a minority of patients ultimately proceed to allo-HCT. The primary objective of this prospective, observational study was to identify the rate of allo-HCT in patients for whom it was recommended, and reasons why patients deemed appropriate and eligible for HCT did not subsequently undergo transplant. Between April 2016 and April 2021, adult patients with newly diagnosed or relapsed/refractory acute leukemia were enrolled at the time of induction/reinduction therapy. Initial transplantation workup and allo-HCT recommendations were made during the early phase of induction/reinduction. Of the 307 enrolled patients, allo-HCT was recommended to 85% (n = 259), of whom 66% (n = 170) underwent transplant. Donor sources comprised 54% human leukocyte antigen (HLA)-matched unrelated donors, 20% HLA-matched sibling donors and HLA-mismatched graft sources with 15% umbilical cord blood units, 8% HLA-mismatched unrelated donors, and 4% HLA-haploidentical donors. The most common reason for transplant disqualification in the 89 patients in whom it was initially recommended was persistent/relapsed disease (70%), followed by early patient death (10%). In this prospective study, we report a high allo-HCT rate, which may be due to early transplant referral and workup. The main allo-HCT barrier was disease control, followed by early patient death. With the increasing availability of HLA-mismatched graft sources, the lack of donor availability was not a transplant barrier. Further development of novel transplant strategies for patients not achieving remission and improvements in induction regimens could result in increased allo-HCT utilization.

DOI: https://doi.org/10.1002/ajh.27084
Cell Rep. 2023 Sep 06. pii: S2211-1247(23)01092-6. [Epub ahead of print] 113081

The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.

Rowan A Boyd, Saurav Majumder, Johnny Stiban, Grace Mavodza, Alexandra J Straus, Sachin K Kempelingaiah, Varun Reddy, Yusuf A Hannun, Lina M Obeid, Can E Senkal.

  Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.

Keywords:  C18-ceramide; CP: Molecular biology; CerS1; Hsp27; ceramide; ceramide synthase; mitophagy; sphingolipids

DOI:  https://doi.org/10.1016/j.celrep.2023.113081
iScience. 2023 Sep 15. 26(9): 107583

CD82 expression marks the endothelium to hematopoietic transition at the onset of blood specification in human.

Sara Menegatti, Bethany Potts, Roberto Paredes, Eva Garcia-Alegria, Syed Murtuza Baker, Valerie Kouskoff.

  During embryonic development, all blood progenitors are initially generated from endothelial cells that acquire a hemogenic potential. Blood progenitors emerge through an endothelial-to-hematopoietic transition regulated by the transcription factor RUNX1. To date, we still know very little about the molecular characteristics of hemogenic endothelium and the molecular changes underlying the transition from endothelium to hematopoiesis. Here, we analyzed at the single cell level a human embryonic stem cell-derived endothelial population containing hemogenic potential. RUNX1-expressing endothelial cells, which harbor enriched hemogenic potential, show very little molecular differences to their endothelial counterpart suggesting priming toward hemogenic potential rather than commitment. Additionally, we identify CD82 as a marker of the endothelium-to-hematopoietic transition. CD82 expression is rapidly upregulated in newly specified blood progenitors then rapidly downregulated as further differentiation occurs. Together our data suggest that endothelial cells are first primed toward hematopoietic fate, and then rapidly undergo the transition from endothelium to blood.

Keywords:  Cell biology; Developmental biology; Molecular biology; Stem cells research; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107583
Br J Haematol. 2023 Sep 11.

Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.

Maria Agustina Perusini, Igor Novitzky-Basso, Eshetu G Atenafu, Donna Forrest, Isabelle Bence-Bruckler, Lynn Savoie, Mary-Margaret Keating, Lambert Busque, Robert Delage, Anargyros Xenocostas, Elena Liew, Pierre Laneuville, Kristjan Paulson, Tracy Stockley, Jeffrey H Lipton, Brian Leber, Dennis Dong Hwan Kim.

  Multiple studies have reported a significant treatment-free remission (TFR) rate of 50%-60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re-initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re-therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post-imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach.

Keywords:  CML; TKI discontinuation; treatment-free remission

DOI:  https://doi.org/10.1111/bjh.19058
Cell. 2023 Sep 14. pii: S0092-8674(23)00904-2. [Epub ahead of print]186(19): 4005-4006

Getting an aMPLe grasp on hematopoiesis.

Samantha Joubran, Vijay G Sankaran.

Hematopoiesis requires balance between self-renewal of stem cells and differentiation into mature blood cells, orchestrated by pathways such as thrombopoietin signaling. In this issue of Cell, Tsutsumi et al. report the structure of the thrombopoietin ligand-receptor complex and demonstrate the potential to decouple its roles in self-renewal and hematopoietic differentiation.

DOI: https://doi.org/10.1016/j.cell.2023.08.015
Leukemia. 2023 Sep 15.

Persistence of ex vivo expanded tumour and pathogen specific T-cells after allogeneic stem cell transplant for myeloid malignancies (the INTACT study).

Wei Jiang, Selmir Avdic, Koon H Lee, Janine Street, Gloria Castellano-González, Renee Simms, Leighton E Clancy, Richard Blennerhassett, Ellis Patrick, Adam S Chan, Helen M McGuire, Nadav Myers, Brian S Gloss, Melissa Gabriel, Caroline M Bateman, Ken Micklethwaite, David J Gottlieb, Emily Blyth.

DOI: https://doi.org/10.1038/s41375-023-02033-5
Nature. 2023 Sep 13.

Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome.

Zhikuan Zhang, Takuma Shibata, Akiko Fujimura, Jiro Kitaura, Kensuke Miyake, Umeharu Ohto, Toshiyuki Shimizu.

Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis1. NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer2-6. However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated4,7,8. Here we identify ubiquitously expressed endogenous thioredoxin (TRX) as a binder of NLRP1 and a suppressor of the NLRP1 inflammasome. The cryo-electron microscopy structure of human NLRP1 shows NLRP1 bound to Spodoptera frugiperda TRX. Mutagenesis studies of NLRP1 and human TRX show that TRX in the oxidized form binds to the nucleotide-binding domain subdomain of NLRP1. This observation highlights the crucial role of redox-active cysteines of TRX in NLRP1 binding. Cellular assays reveal that TRX suppresses NLRP1 inflammasome activation and thus negatively regulates NLRP1. Our data identify the TRX system as an intrinsic checkpoint for innate immunity and provide opportunities for future therapeutic intervention in NLRP1 inflammasome activation targeting this system.

DOI: https://doi.org/10.1038/s41586-023-06532-4