bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒09‒24
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

  1. Blood Cancer J. 2023 Sep 21. 13(1): 149
      We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1-mutated patients with clonal cytopenia of undetermined significance (CCUS; n = 22), MDS (n = 108), MDS/acute myeloid leukemia (AML; n = 18) and AML (n = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML (P = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS/KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F (n = 97) and Q157P (n = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P = 0.01) and abnormal karyotype with the former (70% vs 62%; P = 0.05). U2AF1 S34F MT clustered with BCOR (P = 0.04) and Q157P MT with ASXL1 (P = 0.01) and TP53 (P = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease (n = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F (P = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P (P = 0.01) on survival and also identified JAK2 MT as an additional risk factor (P = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.
  2. Blood. 2023 Sep 22. pii: blood.2023019782. [Epub ahead of print]
      Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53 mutated AML, we identified polo-like kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms and therapeutic potential in TP53 mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wildtype AML and was increased in TP53 mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wildtype AML. Prolonged PLK4 inhibition suppressed the growth of TP53 mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wildtype and mutated AML, resulting in histone modification through PLK4 induced PRMT5 phosphorylation. In TP53 mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon co-culture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53 mutated AML.
  3. Nat Commun. 2023 09 19. 14(1): 5709
      The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies.
  4. Crit Rev Oncol Hematol. 2023 Sep 15. pii: S1040-8428(23)00227-5. [Epub ahead of print] 104139
      FMS-like tyrosine kinase 3 (FLT3) mutations occur in almost 30% of acute myeloid leukemia (AML) patients. Despite the initial clinical efficacy of FLT3 inhibitors, many treated AML patients with mutated FLT3 eventually relapse. This review critically discusses the potential and challenges of FLT3-targeted therapies and sheds light on their drug interactions as well as potential biomarkers. Furthermore, we focus on the molecular mechanisms underlying the resistance of FLT3 internal tandem duplication (FLT3-ITD) AMLs to FLT3 inhibitors alongside novel therapeutic strategies to reverse resistance. Notably, dynamic heterogeneous patterns of clonal selection and evolution contribute to the resistance of FLT3-ITD AMLs to FLT3 inhibitors. Ongoing preclinical research and clinical trials are actively directed towards devising rational "personalized" or "patient-tailored" combinatorial therapeutic regimens to effectively treat patients with FLT3 mutated AML.
    Keywords:  AML; Biomarker; Drug interaction; FLT3 mutation; Resistance; Toxicity
  5. Br J Haematol. 2023 Sep 19.
      Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.
    Keywords:  DNA hypomethylating agents; DNA methylation; interferon response; leukaemia stem cells; myeloproliferative neoplasm; secondary acute myeloid leukaemia; viral mimicry
  6. Blood Adv. 2023 Sep 20. pii: bloodadvances.2022008899. [Epub ahead of print]
      Acute megakaryoblastic leukemia (AMKL) is a rare, developmentally restricted and highly lethal cancer of early childhood. The paucity and hypocellularity (due to myelofibrosis) of primary patient samples hamper the discovery of cell- and genotype-specific treatments. AMKL is driven by mutually exclusive chimeric fusion oncogenes in two thirds of cases, with CBFA2T3::GLIS2 (CG2) and NUP98 fusions (NUP98r) representing the highest fatality subgroups. We established CD34+ cord blood-derived CG2 models (n=6) that sustain serial transplantation and recapitulate human leukemia regarding immunophenotype, leukemia initiating cell frequencies, co-mutational landscape and gene expression signature with distinct upregulation of the pro-survival factor BCL2. Cell membrane proteomic analyses highlighted CG2 surface markers preferentially expressed on leukemic cells compared to CD34+ cells (e.g. NCAM1, CD151). AMKL differentiation block in the mega-erythroid progenitor space was confirmed by single cell profiling. While CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with Venetoclax, they were vulnerable to strategies that target the megakaryocytic pro-survival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor Navitoclax and DT2216, a selective BCL-XL PROTAC (proteolysis-targeting chimera) degrader developed to limit thrombocytopenia in patients. NUP98r AMKL were also sensitive to BCL-XL inhibition, but not the NUP98r monocytic leukemia, pointing to a lineage-specific dependency. Navitoclax or DT2216 treatment in combination with low dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL.
  7. Sci Adv. 2023 Sep 22. 9(38): eadg0488
      Measurable residual disease (MRD), defined as the population of cancer cells that persist following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones, and normal precursors remains a challenge with current MRD tools. Here, we developed a single-cell MRD (scMRD) assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated single-cell DNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture, and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/preleukemic and leukemic cells surviving acute myeloid leukemia therapy.
  8. medRxiv. 2023 Sep 05. pii: 2023.09.04.23295042. [Epub ahead of print]
      TP53 mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations impact disease biology, and whether they differ between disease categories, remain unknown. We analyzed TP53 mutations in four myeloid neoplasm subtypes (MDS, AML, AML with myelodysplasia-related changes (AML-MRC), and therapy-related acute myeloid leukemia (tAML)), and identified differences in mutation types, spectrum, and hotspots between disease categories and compared to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC compared to MDS. TP53 mutations in MDS were more likely to retain transcriptional activity, and co-mutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutated TP53 contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification of TP53 mutations in myeloid malignancies.Statement of Significance: The distribution and functional consequences of TP53 mutations differ between hematologic malignancies and solid tumors, and, among myeloid neoplasms, between myelodysplastic syndrome and acute leukemia. These findings suggest distinct biological mechanisms for mutated p53 in hematologic malignancies, specifically in initiation and progression of myeloid neoplasia, that warrant further investigation.
  9. Blood. 2023 Sep 20. pii: blood.2023021503. [Epub ahead of print]
      Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis with low-risk PV patients treated with therapeutic phlebotomy and aspirin alone, while cytoreductive therapy with either hydroxyurea or interferon (IFN)-α is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in otherwise low-risk patients. Additionally, recent studies demonstrating the safety and efficacy (i.e., reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α-2b support its use in low-risk PV patients. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this review, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately impact the natural history of the disease.
  10. Leukemia. 2023 Sep 19.
      Therapy after failing response milestones in CML is controversial. Risks associated with comorbidities, drug toxicities or transplantation may preclude switching to another tyrosine kinase inhibitor (TKI) or other treatments. No information on long-term survival of failing patients is available. To systematically analyse survival after reaching, or not reaching, response milestones, 1342 patients from CML-study IV with newly diagnosed CML in chronic phase and regular molecular tests were studied. Landmark survival analyses were done by <0.1%, 0.1-1%, >1-10% and >10% BCR::ABL1IS at 3, 6, 12 and 24 months up to 14 years. 10- to 12-year survival of patients who failed the failure milestones (>10% BCR::ABL1IS at 6 months, >1% BCR::ABL1IS at 12 months) ranged around 80%, 10% less than in responding patients. These results suggest revision of milestones. Age (more or less than 60 years) had no major impact on survival differences, but on hazard ratios and CML-specific survival. Switching to alternative therapies, which was observed in 26.9% of the patients, did not change the main results. The data show that TKI-treated patients not reaching failure milestones still may derive benefit from continuing TKI-treatment and provide a basis for individualised decisions, if failing patients are confronted with risks of alternative treatments.
  11. Ann Hematol. 2023 Sep 18.
      Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.
    Keywords:  Aclarubicin; Acute myeloid leukemia; Homoharringtonine; Hypomethylating agents; Priming regimens; Venetoclax
  12. Cancer Discov. 2023 Sep 22. OF1
      Chronic inflammation enhances the fitness advantage of TP53-mutant cells and promotes genetic evolution.
  13. Sci Adv. 2023 Sep 22. 9(38): eadk2533
      A novel multiplex single-cell genomic and immunophenotypic strategy leverages the sensitivity of MRD detection and distinguishes leukemic and preleukemic subpopulations.
  14. Cell Rep. 2023 Sep 08. pii: S2211-1247(23)01095-1. [Epub ahead of print] 113084
      Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL.
    Keywords:  BCL2; CBFA2T3-GLIS2; CP: Cancer; ETO2-GLIS2; Ras; acute megakaryoblastic leukemia; apoptosis; mouse model; navitoclax; pediatric cancer
  15. Cell Commun Signal. 2023 Sep 22. 21(1): 255
      Chemoresistance poses a significant impediment to effective treatment strategies for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our previous study unveiled that oncogene TWIST1 interacted with DNA methyltransferase 3a (DNMT3a) to regulate the decitabine (DAC) resistance in MDS/AML. However, the underlying mechanism of TWIST1 dysregulation in DAC resistance remained enigmatic. Here, we found that O-GlcNAc modification was upregulated in CD34+ cells from MDS/AML patients who do not respond to DAC treatment. Functional study revealed that O-GlcNAcylation could stabilize TWIST1 by impeding its interaction with ubiquitin E3 ligase CBLC. In addition, as one typical transcription factor, TWIST1 could bind to the promoter of O-GlcNAc transferase (OGT) gene and activate its transcription. Collectively, we highlighted the crucial role of the O-GlcNAcylated TWIST1 in the chemoresistance capacity of MDS/AML clonal cells, which may pave the way for the development of a new therapeutic strategy targeting O-GlcNAcylated proteins and reducing the ratio of MDS/AML relapse. Video Abstract.
    Keywords:  DAC resistance; MDS/AML; O-GlcNAc; OGT; TWIST1
  16. medRxiv. 2023 Sep 07. pii: 2023.09.05.23295093. [Epub ahead of print]
      Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.
  17. Nat Commun. 2023 Sep 21. 14(1): 5871
      The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3' end of the PNT (pointed) domain, in ERG's ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG's interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.
  18. Sci Rep. 2023 Sep 20. 13(1): 15658
      Acute myeloid leukemia (AML) is characterized by an unfavorable prognosis due to the presence of self-renewing leukemic stem cells (LSCs). The presence of T-cell immunoglobulin mucin-3 (TIM-3) on the surface of LSCs has been observed in various types of human AML, exerting an impact on the prognostic outcome. Exploring the hub genes associated with varying levels of TIM-3 expression offers a valuable approach to enhance our understanding of the underlying mechanisms involving TIM-3 and to identify potential prognostic indicators in AML. Nevertheless, to date, no research studies have reported a prognostic model that relies on the level of TIM-3 expression. In our study, we screen the hub-genes based on different expression level of TIM-3 through WGCNA. The prognostic risk-scoring model was constructed based on hub-genes. The results show the risk prognostic model has extraordinary ability to predict prognosis in both the training and validation sets. The high-risk group present poor prognosis with mutation of NPM1, TP53 (Multiple Hit) and FLT3(multiple hit), while IDH2 (Missense Mutation), MUC16 (Multiple Hit/Missense Mutation) occur mutation in low-risk group presenting favorite prognosis than high-risk group. Leukocyte cell-cell adhesion, regulation of T cell activation and I-κB kinase/NF-κB signaling enriched in high-risk group, involving in HSCs or LSCs anchoring to BM, which implicated in LSCs survival and chemotherapy resistance. B7-H3 (CD276) and CD276 would be the potential immune targets in high-risk group. The risk score model may help in distinguishing immune and molecular characteristics, predicting patient outcomes.
  19. Hematol Oncol. 2023 Sep 20.
      The CFA ratio, calculated using pretreatment C-reactive protein (CRP), fibrinogen, and albumin levels (CRP × fibrinogen/albumin), was previously reported to be a significant prognostic factor for acute myeloid leukemia (AML). This multicenter retrospective study evaluated the prognostic value of the CFA ratio in 328 adult patients with newly diagnosed AML from April 2000 to March 2018. The median age was 49.5 years (range, 15-75 years), and 60.7% of the population were males. According to the European LeukemiaNet (ELN) risk classification, 67 patients (20.4%) were in the favorable-risk group, 197 patients (60.1%) in the intermediate-risk group, and 58 patients (17.7%) in the adverse-risk group. The median CFA ratio was 1.07 (0-67.69). Based on the calculated cutoff CFA ratio of 1.44, the cohort included 176 and 152 patients with low and high CFA ratios, respectively. At a median follow-up of 91.2 months, the 7-year overall survival (OS) and disease-free survival (DFS) rates were 51.2% and 48.6%, respectively, in the overall cohort. The 7-year OS rates were 61.7% and 39.0% in the low and high CFA ratio groups, respectively (p < 0.001). The 7-year DFS rates were 58.1% and 37.0% in the low and high CFA ratio groups, respectively (p = 0.004). In univariate analysis, age ≥50 years, male sex, ELN risk class, and comorbidities were associated with poor OS. Age, ELN risk class, comorbidities, and high CFA ratio were associated with poor OS in multivariate analysis. Subgroup analysis revealed that the CFA ratio was significant in the intermediate and adverse ELN risk classes. These findings indicate the prognostic significance of the CFA ratio in AML.
    Keywords:  C-reactive protein; CFA ratio; acute myeloid leukemia; albumin; fibrinogen; prognosis
  20. Blood Adv. 2023 Sep 20. pii: bloodadvances.2023011050. [Epub ahead of print]
      Preexisting autoimmune disease affects 10-30% of patients with myelodysplastic syndromes (MDS). Studies comparing outcomes in MDS patients with and without autoimmune disease show discordant results. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare, we conducted a population analysis to define the impact of autoimmunity on MDS outcomes. Cases were ascertained between 2007 - 2017 and claim algorithms employed to identify autoimmune disease, demographic characteristics, comorbidity scores, MDS histology, transfusion burden, treatment with hypomethylating agents and hematopoietic stem cell transplant. Cox regression models estimated the impact on survival and competing-risk regression models defined the effect on leukemic transformation. We analyzed 15,277 MDS patients, including 2,442 (16%) with preexisting autoimmune disease. The epidemiologic profile was distinctive in cases with preexisting autoimmunity, who were younger, predominantly female and had higher transfusion burden without difference in MDS histologic distribution. Autoimmune disease was associated with 11% decreased risk of death (hazard ratio [HR] 0.89, 95% confidence interval [CI], 0.85 - 0.94, p<0.001). The effect on risk of leukemic transformation differed based on MDS histology. In low-risk MDS histologies, autoimmunity was associated with a 1.9-fold increased risk of leukemia (HR 1.87, 95%CI, 1.17 - 2.99, p=0.008), while no significant effect was seen in other groups. These results suggest that autoimmune disease affects survival in MDS and is associated with decreased mortality. The survival effect was evident in low risk histologies despite higher risk of progression to leukemia. This could represent inflammation-driven hematopoiesis simultaneously favoring less aggressive phenotypes and clonal expansion, which warrants further investigation.
  21. Nature. 2023 Sep 20.
      Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.
  22. JCO Precis Oncol. 2023 Sep;7 e2300208
      PURPOSE: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC).METHODS: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA.
    RESULTS: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC.
    CONCLUSION: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.
  23. Haematologica. 2023 Sep 21.
      Acute myeloid leukemia (AML) is a hematological malignancy that frequently relapses, even if remission is achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic cells from immune surveillance. Currently, there is no effective AML immunotherapy owing to the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and their therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 AML cases indicated that high expression of CD112 is associated with shorter survival than low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhances the expression of cytotoxicity-related genes, thus overcoming TIGIT inhibitory activity. Between CD155 and CD112, CD112 is an especially important target for NK cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also revealed that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, the modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, these results suggest the potential of the expression levels of these molecules as prognostic markers in AML.
  24. Exp Hematol. 2023 Sep 16. pii: S0301-472X(23)01704-6. [Epub ahead of print]
      Sterile alpha motif domain-14 (Samd14) protein expression increases the regenerative capacity of the erythroid system. In a critical window of acute erythroid regeneration, Samd14 is transcriptionally upregulated and promotes cell signaling via the receptor tyrosine kinase Kit. We generated a hematopoietic-specific conditional Samd14 knockout mouse model (Samd14-CKO) to study the role of Samd14 in hematopoiesis. The Samd14-CKO mouse was viable and exhibited no steady-state hematopoietic phenotype. Samd14-CKO mice were hypersensitive to 5-fluorouracil, resulting in more severe anemia during recovery and impaired erythroid progenitor colony formation. Ex vivo, Samd14-CKO hematopoietic progenitors were defective in their ability to form mast cells. Samd14-CKO mast cells exhibited altered Kit/SCF, IL-3/IL-3R signaling, and less granularity compared to Samd14-FL/FL cells. Our findings indicate that Samd14 promotes both erythroid and mast cell functions. The Samd14-CKO mouse phenotype exhibits striking similarities to the KitW/W-v mice, which carry Kit mutations resulting in reduced tyrosine kinase-dependent signaling, causing mast cell and erythroid abnormalities. The Samd14-CKO mouse model is a new tool for studying hematologic pathologies involving Kit signaling.
    Keywords:  erythropoiesis; mast cell; receptor tyrosine kinase signaling; regeneration
  25. Blood Adv. 2023 Sep 20. pii: bloodadvances.2022008347. [Epub ahead of print]
      Hemogenic endothelial cells (HECs) are specialized cells that undergo endothelial to hematopoietic transition (EHT) to give rise to the earliest precursors of hematopoietic progenitors that will eventually sustain hematopoiesis throughout the lifetime of an organism. Although HECs are thought to be primarily limited to the aorta gonad mesonephros (AGM) during early development, EHT has been described in various other hematopoietic organs and embryonic vessels. Though not defined as a hematopoietic organ, the lung houses many resident hematopoietic cells, aids in platelet biogenesis, and is a reservoir for hematopoietic stem and progenitor cells (HSPCs). However, lung HECs have never been described. Here we demonstrate that the fetal lung is a potential source of HECs that have the functional capacity to undergo EHT to produce de novo HSPCs and their resultant progeny. Explant cultures of murine and human fetal lungs display adherent endothelial cells transitioning into floating hematopoietic cells accompanied by the gradual loss of an endothelial signature. Flow cytometric and functional assessment of fetal lung explants showed the production of multipotent HSPCs that expressed the EHT and pre-HSPC markers EPCR, CD41, CD43 and CD44. scRNA-Seq and small molecule modulation demonstrated that fetal lung HECs rely on canonical signaling pathways to undergo EHT, including TGFβ/BMP, Notch and YAP. Collectively, these data support the possibility that post-AGM development, functional HECs are present in the fetal lung establishing this location as a potential extramedullary site of de-novo hematopoiesis.
  26. Science. 2023 Sep 22. 381(6664): 1316-1323
      Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.