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Abstract A18: STC-15, a novel METTL3 inhibitor, and its combination with Venetoclax confer anti-tumour activity in AML models 摘要:STC-15是一种新型METTL3抑制剂,它与Venetoclax联合在AML模型中具有抗肿瘤活性
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a18
L. Vasiliauskaitė, Y. Ofir-Rosenfeld, M. Albertella, C. Hoareau-Aveilla, Jerry McMahon, Oliver Rausch
{"title":"Abstract A18: STC-15, a novel METTL3 inhibitor, and its combination with Venetoclax confer anti-tumour activity in AML models","authors":"L. Vasiliauskaitė, Y. Ofir-Rosenfeld, M. Albertella, C. Hoareau-Aveilla, Jerry McMahon, Oliver Rausch","doi":"10.1158/2643-3249.aml23-a18","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a18","url":null,"abstract":"\u0000 N6-methyladenosine (m6A) is one of the most abundant RNA modifications, which influences mRNA and lncRNA localization, half-life, translation, and splicing. The majority of m6A modifications on cellular mRNAs are deposited by the RNA methyltransferase METTL3. To date, METTL3 has been implicated in the initiation and progression of multiple cancer types, with the highest expression of METTL3 mRNA observed in acute myeloid leukemia (AML). Currently, one line of standard of care therapy for AML patients is Venetoclax, which targets the anti-apoptotic protein BCL2. It was shown that m6A, deposited by METTL3 on BCL2 transcript, affects BCL2 mRNA stability and translation. Storm Therapeutics has developed potent and selective METTL3 inhibitors, including the clinical candidate STC-15. Here, we explore pharmacological inhibition of METTL3 as monotherapy or in combination with Venetoclax in AML models in vitro and in vivo. Sulforhodamine B and CellTiterGloTM assays were used to assess the viability of AML cell lines and patient-derived xenografts (PDXs), respectively, following METTL3 inhibition in vitro. BCL2 protein level was evaluated by Western blotting. SynergyFinder software was used to assess the degree of synergy between METTL3 inhibitors and Venetoclax. Intra-tibial implantation of human-derived AML cells (AML-PDXs) in NSG mice was used to determine single agent and combination therapy efficacy. Multiple AML cells lines and AML-PDXs were sensitive to pharmacological inhibition of METTL3 in vitro, as assessed by loss of viability. Treatment with METTL3 inhibitors led to downregulation of BCL2 protein level in several AML cell lines, as previously suggested by literature. Based on these results, the synergy between METTL3 inhibition and Venetoclax was assessed. Matrix-combination experiments have shown a high degree of synergy between the two drugs (defined by a synergy score >10) in THP-1 and MOLM-13 cell lines. To test METTL3 inhibition as a monotherapy and in combination with Venetoclax in vivo, three AML-PDX studies were initiated. Significantly lower spleen weight was observed in all animals treated with STC-15 or STC-15 + Venetoclax, and reduced number of circulating hCD45+ cells was observed in 2 out of the 3 models. In one of the models, STC-15 monotherapy outperformed Venetoclax (median survival 68 days vs 58 days, respectively), while the combination therapy extended median group survival to 85 days in comparison to 51.5 days in the vehicle group. In conclusion, we demonstrated that METTL3 inhibition results in anti-tumour effects across different AML models. Moreover, we demonstrated a synergistic effect between the novel METTL3 inhibitor STC-15 and Venetoclax, both in vitro and in vivo. These studies provide evidence for the utility of METTL3 inhibitor as a new therapeutic agent to treat AML. Currently, STC-15 is under clinical development (NCT05584111).\u0000 Citation Format: Lina Vasiliauskaite, Yaara Ofir-Rosenfeld, Mark Albertella, Co","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46808001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A52: IDS and SETBP1 is highly prognostic in myelodysplastic neoplasms and is a candidate stem cell signature 摘要:IDS和SETBP1在骨髓增生异常肿瘤中具有高度预后作用,是一种候选的干细胞特征
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a52
A. Ediriwickrema, A. Gentles, R. Majeti
{"title":"Abstract A52: IDS and SETBP1 is highly prognostic in myelodysplastic neoplasms and is a candidate stem cell signature","authors":"A. Ediriwickrema, A. Gentles, R. Majeti","doi":"10.1158/2643-3249.aml23-a52","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a52","url":null,"abstract":"\u0000 Myelodysplastic neoplasms (MDS) are heterogenous blood disorders that arise from dysfunctional hematopoietic stem cells (HSCs) and progenitor cells (HSPCs). According to the cancer stem cell (CSC) model, MDS is organized as a cellular hierarchy that arises from the malignant transformation of HSPCs into rare CSCs. MDS-CSCs are thought to persist during treatment and regenerate disease during relapse. Prior studies have linked MDS-CSCs to MDS-HSPC (Woll et al. Cancer Cell 2014, Pang et al, PNAS 2013, Will et al, Blood 2012), however, a specific cell type has not been isolated and purified as the MDS-CSC. Prognostic gene expression signatures in MDS have also been linked to immature HSPCs (Shiozawa et al, Blood 2017), however, a cell specific signature has not been identified. There is a need to characterize a cell specific gene signature for MDS-CSCs in order to study these cells. To address this need, we performed iterative statistical analyses on MDS gene expression data in order to identify a candidate CSC signature. We hypothesized that by analyzing genes specifically up-regulated in MDS-HSPCs, we can derive a CSC specific gene signature that is not only associated with poor outcomes in MDS, but also marks a subset of cells in MDS with stem cell programs. Up-regulated genes in MDS-HSPCs compared to healthy controls were derived by re-analyzing 73 sorted samples (Woll et al, Cancer Cell 2014) using the limma (Ritchie et al, Nucleic Acids Res 2015). Using these genes, we subsequently analyzed their association with survival in a cohort of 244 MDS patients (Shiozawa et al, Blood 2017, Gerstung et al, Nat Commun 2015, Tyner et al, Nature 2018). We performed iterative Cox proportional hazard models on a training data (n=146), using single and multiple gene combinations. A 2 gene score (i.e., MDS2), comprising IDS and SETBP1, was identified as the most significantly associated feature with decreased survival in MDS compared to Age, Sex, Cytogenetic Risk, and an established MDS score (Shiozawa et al, Blood 2017). Single cell expression of MDS2 was evaluated in MDS scRNA-seq samples (Dussiau et al, BMC Biol2022), and rare cells were identified expressing high levels of MDS2, i.e., MDS2 cells. These cells were integrated with healthy HSPCs. MDS2 cells reside primarily between HSCs and MPPs on a diffusion map, following a differentiation trajectory towards GMPs and monocyte precursors. These observations are consistent with prior studies, as MDS-CSCs were shown to be enriched in HSCs and GMPs (Pang et al, PNAS 2013, Woll et al, Cancer Cell 2014). Analysis of upregulated genes in MDS2 cells revealed that antigen processing, assembly and presentation were the most enriched processes. This analysis supports our approach for identifying a cell specific gene signature, and future work will focus on further single cell analyses and evaluation of CSC content and function of MDS2 cells.\u0000 Citation Format: Asiri Ediriwickrema, Andrew Gentles, Ravindra Majeti. I","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47387308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A25: A niche directed therapy for the treatment of myelodysplasia and acute myeloid leukemia 摘要A25:一种治疗骨髓发育不良和急性髓系白血病的小生境定向疗法
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a25
I. Mosialou, A. Ali, Rachel Adams, A. Corper, C. Woods, Xiaomin Fan, A. Raza, S. Kousteni
{"title":"Abstract A25: A niche directed therapy for the treatment of myelodysplasia and acute myeloid leukemia","authors":"I. Mosialou, A. Ali, Rachel Adams, A. Corper, C. Woods, Xiaomin Fan, A. Raza, S. Kousteni","doi":"10.1158/2643-3249.aml23-a25","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a25","url":null,"abstract":"\u0000 Cells of the surrounding bone marrow microenvironment (niche) have emerged as important regulators of myeloid disease development and progression, leading to myeloproliferative neoplasms, myelodysplasia (MDS) or acute myeloid leukemia (AML). This not only highlights the complexity of the disease but may, at least in part, explain the limitations of current malignant cell targeted therapies to prevent relapse and at the same time opens new avenues for therapeutic intervention. To test this hypothesis, we examined here the therapeutic potential of targeting a potent, niche-driven oncogenic pathway, constitutive activation of b-catenin/Jagged1 signaling in osteoblasts. In humans, this pathway is activated in approximately 40% of MDS and AML patients; and also following hypermethylation of its regulators in MDS patients. Its activation levels increase with disease severity, correlate with MDS to AML transformation and with del(5q)-associated myeloid malignancies. In mice, it leads to MDS rapidly progressing to AML. To test its therapeutic potential, we inhibited Jagged1. We generated a chimeric human-mouse neutralizing antibody that efficiently and specifically binds JAG1 (anti-JAG1) and inhibits Notch1-induced signaling. Administration of anti-JAG1 in leukemic mice with activated b-catenin/Jag1 in their osteoblasts rescued anemia, thrombocytopenia, neutrophilia and lymphocytopenia, relieved myeloid differentiation block and eliminated blasts. Body weight increased with time and lethality was abrogated in treated mice. Blood chemistry profiling indicated lack of any toxicity following treatment as indicated by normal liver and kidney function and absence of inflammation, dyslipidemia or pancreatitis. In contrast, chemotherapy at a dose simulating the induction regimen used in patients, dramatically exacerbated anemia, thrombocytopenia and lymphocytopenia without decreasing blasts leading to increased lethality due to bone marrow failure. Emphasizing relevance to human disease, anti-JAG1 treatment of patient-derived samples with activated b-catenin/JAG1 in their osteoblasts, inhibited MDS and AML cell growth and survival and promoted myeloid and erythroid differentiation through its actions on osteoblasts. Responsiveness was observed across patients belonging to diverse disease subtypes and categories including patients with adverse cytogenetics and high-risk groups. Confirming the specificity of anti-JAG1 action, no effect was observed in cells from patients without activated b-catenin/JAG1 in their osteoblasts or healthy subjects and the magnitude of the response correlated with the levels of b-catenin/JAG1 activation in osteoblasts. These results suggest the therapeutic efficacy of blocking JAG1 and its superiority to chemotherapy in osteoblastic, b-catenin-driven MDS/AML that could impact 1/3 of MDS and AML patients. In addition, they suggest that targeting the niche may be an approach to avoid toxicity and overcome MDS/AML cell mutation depende","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43208476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A41: Single Cell Multiomic Analysis Reveals Association of TP53-mut Loss of Heterozygosity with Primitive Phenotype in Acute Myeloid Leukemia 摘要A41:单细胞多组分析揭示急性髓细胞白血病中TP53-mut杂合性缺失与原始表型的相关性
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a41
Edward Ayoub, V. Mohanty, Yuki Nishida, Tallie Patsilevas, Mahesh Basyal, Russell Pourebrahim, M. Muftuoglu, Ken Chen, G. Issa, M. Andreeff
{"title":"Abstract A41: Single Cell Multiomic Analysis Reveals Association of TP53-mut Loss of Heterozygosity with Primitive Phenotype in Acute Myeloid Leukemia","authors":"Edward Ayoub, V. Mohanty, Yuki Nishida, Tallie Patsilevas, Mahesh Basyal, Russell Pourebrahim, M. Muftuoglu, Ken Chen, G. Issa, M. Andreeff","doi":"10.1158/2643-3249.aml23-a41","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a41","url":null,"abstract":"\u0000 TP53 mutations in acute myeloid leukemia (AML) are associated with copy number abnormalities (CNA), structural variants and high risk of relapse (Döhner et al., 2017; Giacomelli et al., 2018; Bernard et al. 2020). In spite of relatively high remission rates obtained by targeted therapies, TP53 mutant (TP53-mut) clones persist, invariably resulting in relapse (Short et al., 2021; Takahashi et al., 2016). Delineating the clonal architecture and the immunophenotypes of TP53-mut clones during AML therapy may provide a better understanding of the role of TP53-mutations in AML biology. Recent progress in sequencing technologies allows the integration of genotyping and phenotyping at the single cell level. Here, we took advantage of MissionBio Tapestri’s newest platform: single cell DNA + protein for simultaneous genotyping and phenotyping with 45 surface oligo-conjugated antibodies in 10 paired samples from 5 patients with TP53-mut AML before and after therapy. Samples with at least 70% viability were stained with the TotalSeq™-D Human Heme Oncology Cocktail, V1.0. Following surface marker staining, single-cell suspension, encapsulation, and barcoding were performed according to manufacturer’s instruction. For scDNA library preparation, we utilized a validated custom panel (Morita et al. 2020) consisting of 279 amplicons covering recurrent mutations in 37 genes in AML. We sequenced a total of 44,550 cells from 10 samples. We confirmed mutations reported by MD Anderson molecular diagnostic laboratory in the genes covered by the scDNA custom panel. The clonal architecture analysis distinguished between TP53-mut clones with or without loss of heterozygosity (LOH) of the normal TP53 allele. Our data show a primitive immunophenotype in TP53-mut with LOH (LOH+) clones in comparison to TP53-mut LOH- clones. We see 2.4 LOG2FC increase in CD34 and 1.8 LOG2FC increase in CD117 (p<0.001) in TP53-mut LOH+ clones in comparison to TP53-mut LOH- clones. Clonal evolution analysis shows that TP53-mut LOH+ clones are significantly more resistant to therapy than TP53-mut LOH-, consistent with previous publications. On the other hand, TP53-mut LOH- clones showed significantly higher levels of CD2, CD16, CD5, CD3, and CD8 among other lineage markers (LOG2FC= 1.1, 1.2, 1.4, 1.1, and 1.1 respectively; p.value <0.0001) compared to TP53-mut LOH+. This data indicates that TP53-mut LOH- cells can express lymphoid phenotypic markers. Single cell cytokine analysis (IsoPlexis) reveals profound lack of secreted cytokines in T-cells from TP53-mut AML. Further data from bulk-RNA sequencing, ddPCR, and CyTOF will be presented that validates a lymphoid phenotype of TP53-mut LOH-. In summary, we utilize a scDNA+protein multiomic approach to dissect clonal architecture and provide a link between genotype-phenotype in TP53-mut AML. We show that while TP53-mut LOH+ clones are exclusively primitive, TP53-mut LOH- clones retain the capacity to exist outside primitive immunophenotype and mig","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46643388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A04: Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia 摘要:RNA剪接的调节增强了白血病对BCL2抑制的应答
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a04
Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard
{"title":"Abstract A04: Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia","authors":"Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard","doi":"10.1158/2643-3249.aml23-a04","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a04","url":null,"abstract":"Abstract Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR/Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncovered a selective dependency on RNA splicing factors whose loss preferentially enhanced response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augmented response to venetoclax in leukemia yet was completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition led to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. A novel inhibitor of splicing kinase families CLKs and DYRKs led to aberrant splicing of key splicing and apoptotic factors that synergized with venetoclax and overcame resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments. Citation Format: Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A04.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"52 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136096448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A16: Multi-omic analyses in genetically engineered mice reveal distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells 摘要A16:基因工程小鼠的多组学分析揭示了造血干细胞和祖细胞中致白血病Idh和Tet2突变的不同和相反作用
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a16
J. Fortin, Ming-Feng Chiang, Cem Meydan, J. Foox, P. Ramachandran, Julie Leca, F. Lemonnier, Wanda Li, Miki S Gams, T. Sakamoto, Mandy F. Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, A. You-Ten, D. Butler, T. Berger, M. Minden, R. Levine, C. Guidos, A. Melnick, C. Mason, T. Mak
{"title":"Abstract A16: Multi-omic analyses in genetically engineered mice reveal distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells","authors":"J. Fortin, Ming-Feng Chiang, Cem Meydan, J. Foox, P. Ramachandran, Julie Leca, F. Lemonnier, Wanda Li, Miki S Gams, T. Sakamoto, Mandy F. Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, A. You-Ten, D. Butler, T. Berger, M. Minden, R. Levine, C. Guidos, A. Melnick, C. Mason, T. Mak","doi":"10.1158/2643-3249.aml23-a16","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a16","url":null,"abstract":"\u0000 Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Endogenous Idh2R172K caused much higher D-2-HG production compared to Idh1R132H and Idh2R140Q. This led to profound alterations in hematopoietic progenitor differentiation and to the development of myelodysplastic syndrome-like disease, with shorter survival compared to Tet2−/- mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent and opposite effects on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, which may inform the development of genotype-specific therapies.\u0000 Citation Format: Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, Francois Lemonnier, Wanda Y. Li, Miki S. Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M. Robinson, Annick You-Ten, Daniel J. Butler, Thorsten Berger, Mark D. Minden, Ross L. Levine, Cynthia J. Guidos, Ari M. Melnick, Christopher E. Mason, Tak W. Mak. Multi-omic analyses in genetically engineered mice reveal distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A16.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46359507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A07: Single-cell proteomic assessment of FLT3-ITD AML landscape identifies distinct resistance patterns 摘要:FLT3-ITD AML的单细胞蛋白质组学评估确定了不同的耐药模式
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a07
Li Li, M. Muftuoglu, Mahesh Basyal, N. Daver, M. Andreeff
{"title":"Abstract A07: Single-cell proteomic assessment of FLT3-ITD AML landscape identifies distinct resistance patterns","authors":"Li Li, M. Muftuoglu, Mahesh Basyal, N. Daver, M. Andreeff","doi":"10.1158/2643-3249.aml23-a07","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a07","url":null,"abstract":"\u0000 Acute myeloid leukemia (AML) represents a heterogeneous hematopoietic disorder characterized by accumulation of immature hematopoietic precursors with differentiation block. FLT3 internal tandem duplications (FLT3-ITD) are commonly occurring genetic alterations in AML and are associated with poor prognosis. Preclinical studies showed combining FLT3 inhibitor with MDM2 inhibitor, which is a negative regulator of p53, was synergistic in FLT3-ITD/TP53 wild type (WT) AML. We performed single-cell proteomic evaluation of leukemia landscape in FLT3-ITD patients treated with FLT3i and MDM2i to assess proteomic profiles associated with response and resistance. We performed CyTOF analysis of leukemia cells in serially collected samples from six FLT3-ITD and TP53 WT AML patients following treatment with FLT3i+MDM2i treatment. Using 51 features assessed in CyTOF, we first performed UMAP dimension reduction and clustering to identify distinct cells in leukemia compartment. Notably, the frequencies of blasts identified through CyTOF data analysis were compatible with clinical lab reports. In line with previous reports, we also detected that NPM mutant AML cells did not express CD34. Of note, CD34+ and CD34- leukemia cells were clustered together in NPM1 mut patients, indicating that they have overlapping proteomic profiles. Interestingly, the CD34+ leukemia cells were eliminated at the early time points in CR patients while the CD34- leukemia cells were still detectable after two months. On the other hand, CD34+ leukemia cells in nonresponders(NR) persisted despite therapy. These findings indicate CD34+ leukemia cells were more sensitive to the treatment compared to NPM1 mutant CD34- leukemia cells. Next, we interrogated leukemia proteomic landscape in serial samples, evaluated the therapy-induced alterations in proteomic profiles and sought to identify potential adaptive mechanisms. To this end, we performed differential expression analysis and observed that signaling pathways (p-4EBP1, p-GSK3, p-MEK1/2, p-S6) and differentiation markers(CD33, CD68,CXCR4 HLADR) were more enriched on day 8 post treatment in NR patients, revealing that compensatory signaling activity, phenotypic profiles and differentiation status could be associated with therapy response. Moreover, we found that leukemia cells in NR patients had distinct phenotypic profiles(CD11b,CD68,CXCR4), higher levels of anti-apoptotic molecules (BCL2,MCL1) and enriched survival pathways (p-GSK3, YTHDF2) compared to baseline. In contrast, we did not observe rebound increases in CR patients post-therapy. These findings demonstrate high levels of BCL2 and MCL1 and preferential survival of more differentiated cells may be associated with therapy resistance and treatment failure in NR patient treated with MDM2i and FLT3i. In conclusion, multiplexed single-cell proteomic analysis permitted longitudinal monitoring of leukemia landscape and identified proteomic alterations associated with therapy resistance.\u0000","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43229682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract IA09: Epigenomic landscapes of MDS 摘要IA09:MDS的表观基因组景观
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-ia09
M. Figueroa
{"title":"Abstract IA09: Epigenomic landscapes of MDS","authors":"M. Figueroa","doi":"10.1158/2643-3249.aml23-ia09","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-ia09","url":null,"abstract":"\u0000 While significant progress has been made to understand the genetic landscape of MDS, less is known about the epigenetic makeup of this disease and how this may impact biology and response to azacitidine (AZA). To address this, we performed genomic, epigenomic and transcriptomic analysis on CD34+ cells from a multicenter cohort of 94 intermediate or higher risk MDS patients treated with AZA who had documented responses. DNA methylation (DNAme) by ERRBS, gene expression (GE) by RNA-seq, mutational profiling, and detailed clinical, cytogenetic and laboratory data were documented. Supervised and unsupervised analyses revealed that aberrant DNAme in MDS is not distributed randomly but rather is highly correlated with disease phenotypes, capturing clinically relevant heterogeneity, beyond what is identified by methodologies used in the past that focused solely on promoter regions. Moreover, this epigenetic information can be harnessed for the development of robust biomarkers predictive of AZA response and integrative approaches combining GE and DNAme data can further improve the predictive performance of these biomarkers, with an AUC score=0.92.\u0000 Citation Format: Maria E. Figueroa. Epigenomic landscapes of MDS [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA09.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45018240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target. 体内筛选揭示了白血病干细胞中普遍存在的RNA结合蛋白依赖性,并确定ELAVL1为治疗靶点。
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3230.BCD-22-0086
Ana Vujovic, Laura de Rooij, Ava Keyvani Chahi, He Tian Chen, Brian A Yee, Sampath K Loganathan, Lina Liu, Derek C H Chan, Amanda Tajik, Emily Tsao, Steven Moreira, Pratik Joshi, Joshua Xu, Nicholas Wong, Zaldy Balde, Soheil Jahangiri, Sasan Zandi, Stefan Aigner, John E Dick, Mark D Minden, Daniel Schramek, Gene W Yeo, Kristin J Hope
{"title":"In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target.","authors":"Ana Vujovic,&nbsp;Laura de Rooij,&nbsp;Ava Keyvani Chahi,&nbsp;He Tian Chen,&nbsp;Brian A Yee,&nbsp;Sampath K Loganathan,&nbsp;Lina Liu,&nbsp;Derek C H Chan,&nbsp;Amanda Tajik,&nbsp;Emily Tsao,&nbsp;Steven Moreira,&nbsp;Pratik Joshi,&nbsp;Joshua Xu,&nbsp;Nicholas Wong,&nbsp;Zaldy Balde,&nbsp;Soheil Jahangiri,&nbsp;Sasan Zandi,&nbsp;Stefan Aigner,&nbsp;John E Dick,&nbsp;Mark D Minden,&nbsp;Daniel Schramek,&nbsp;Gene W Yeo,&nbsp;Kristin J Hope","doi":"10.1158/2643-3230.BCD-22-0086","DOIUrl":"10.1158/2643-3230.BCD-22-0086","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an in vivo two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9;NrasG12D AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven in vivo leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell-adapted in vivo CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML.</p><p><strong>Significance: </strong>LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell-adapted in vivo CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. This article is highlighted in the In This Issue feature, p. 171.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"4 3","pages":"180-207"},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9682577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Abstract A51: Divergent effects of MDS predisposing SAMD9L point mutations, in humans, mice, and cellular models 摘要:MDS在人、小鼠和细胞模型中诱发SAMD9L点突变的不同作用
IF 11.2
Blood Cancer Discovery Pub Date : 2023-05-01 DOI: 10.1158/2643-3249.aml23-a51
S. Sahoo, C. Goodings, S. Pruett-Miller, M. Lillo, Lei Han, Baranda S Hansen, T. Chang, T. Lammens, M. Hofmans, Marta Derecka, B. De Moerloose, M. Wlodarski
{"title":"Abstract A51: Divergent effects of MDS predisposing SAMD9L point mutations, in humans, mice, and cellular models","authors":"S. Sahoo, C. Goodings, S. Pruett-Miller, M. Lillo, Lei Han, Baranda S Hansen, T. Chang, T. Lammens, M. Hofmans, Marta Derecka, B. De Moerloose, M. Wlodarski","doi":"10.1158/2643-3249.aml23-a51","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a51","url":null,"abstract":"\u0000 We previously showed that germline SAMD9 and SAMD9L (SAMD9/9L) disorders are the most common predisposition to childhood myelodysplastic syndromes with bone marrow failure (BMF). Heterozygous mutations in both genes are growth inhibitory and undergo negative selection by acquiring compensatory rescue events in blood. Here, we describe the first report of SAMD9L genetic rescue occurring during embryonal development and resulting in germline triple-allelic mosaicism (1 wildtype (WT) and 2 mutant alleles), where only one mutant allele was transmitted to each of the two diseased children. In a family of 2 affected siblings with hypocellular BMF, the Index case carried germline heterozygous SAMD9L V1512M mutation and her brother was heterozygous for V1512L mutation. The clinical presentation for Index with V1512M was more severe compared to her brother with V1512L mutation. Genetic assessment of the parents showed the asymptomatic mother to be a triple-allelic mosaic, carrying WT SAMD9L allele at ~50% frequency in all tissues, while both V1512M and V1512L mutant alleles “competed” in their allelic distribution depending on the tissue origin. Single-cell DNA sequencing on her peripheral blood (PB) revealed 3 independent diploid clones: V1512M in 14%, V1512L in 68%, and WT (due to revertant UPD7q) in 18% of cells. Because her parents were SAMD9L WT, one of the mutations likely arose de novo and underwent failed embryonic rescue attempt leading to a second mutation. Towards studying the effect on hematopoiesis in vitro, we knocked in V1512M and V1512L mutations in inducible pluripotent stem cells (iPSC). For in vivo functional validation, we created constitutive mouse models with ortholog mutations (V1507M and V1507L). Mutant hematopoietic progenitor cells from iPSC had severely compromised proliferative capacity and yielded fewer erythroid and myeloid cells. This effect was more severe in V1512M vs. V1512L mutants. The divergent mutational phenotypes were also replicated in our mouse models: two-thirds (13/19) of the heterozygous V1507M (V1507Mhet) pups died before 4 weeks of age. In contrast, V1507Lhet mice had overall survival equal to WT mice, while one-third of homozygous V1507L (V1507Lhom) mice showed decreased survival post 19 weeks of age. At baseline, V1507Mhet mice showed severe growth retardation with multisystemic issues, which were absent in the V1507L mutant models. PB cytopenia (anemia, B-cell lymphopenia) though observed in both V1507Mhet and V1507Lhom mice, the degree of severity was high in the V1507Mhet than in the V1507Lhom model. Meanwhile, V1507Lhet mice had blood counts similar to WT. In summary, V1512M compared to V1512L mutation resulted in a more severe phenotype in all analyzed model systems. This observation showed how different mutational permutations of the same amino acid can exert divergent phenotypic effects in SAMD9L BMF disorder. Therefore, together with our genetic analysis, we could postulate that the V1512L mutatio","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44706951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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