Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt
{"title":"Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.","authors":"Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt","doi":"10.1158/2643-3230.BCD-24-0001","DOIUrl":"10.1158/2643-3230.BCD-24-0001","url":null,"abstract":"<p><p>In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML.</p><p><strong>Significance: </strong>Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040506","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}
Irene M Ghobrial, Nicole Gormley, Shaji K Kumar, Maria-Victoria Mateos, P Leif Bergsagel, Marta Chesi, Madhav V Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R Marinac, Francesco Maura, Gareth J Morgan, Faith E Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A Shah, Romanos Sklavenitis-Pistofidis, Adam S Sperling, George S Vassiliou, Nikhil C Munshi, Philip E Castle, Kenneth C Anderson, Jesus F San Miguel
{"title":"Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.","authors":"Irene M Ghobrial, Nicole Gormley, Shaji K Kumar, Maria-Victoria Mateos, P Leif Bergsagel, Marta Chesi, Madhav V Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R Marinac, Francesco Maura, Gareth J Morgan, Faith E Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A Shah, Romanos Sklavenitis-Pistofidis, Adam S Sperling, George S Vassiliou, Nikhil C Munshi, Philip E Castle, Kenneth C Anderson, Jesus F San Miguel","doi":"10.1158/2643-3230.BCD-24-0022","DOIUrl":"10.1158/2643-3230.BCD-24-0022","url":null,"abstract":"<p><strong>Summary: </strong>While the current approach to precursor hematologic conditions is to \"watch and wait,\" this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140029182","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}
{"title":"\"Myeloid\" Mutations in ALL Are Not Uncommon: Implications for Etiology and Therapies.","authors":"Ilaria Iacobucci","doi":"10.1158/2643-3230.BCD-24-0015","DOIUrl":"10.1158/2643-3230.BCD-24-0015","url":null,"abstract":"<p><strong>Summary: </strong>In Blood Cancer Discovery, Saygin and colleagues report that somatic variants that are recurrent in myeloid malignancies can also occur with high frequency (16%) in adult acute lymphoblastic leukemia (ALL) where they correlate with older age, diagnosis following genotoxic therapy for a prior malignancy and worse outcome to chemotherapy. Mutations in these \"myeloid\" genes can precede ALL diagnosis and arise in hematopoietic stem or progenitor cells that clonally expand and differentiate into both lymphoblasts and nonmalignant myeloid cells, supporting a role for clonal hematopoiesis as premalignant state outside the context of myeloid malignancies and providing implications for both ALL etiology and therapeutic intervention. See related article by Saygin et al., p. 164 (4).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865548","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}
{"title":"Hematopoietic Clonal Evolution Goes Spatial.","authors":"Rebecca Austin, I. Aifantis","doi":"10.1158/2643-3230.BCD-24-0057","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0057","url":null,"abstract":"SUMMARY\u0000The spatial distribution of cells carrying clonal hematopoiesis mutations in the bone marrow and the potential role of interactions with the microenvironment are largely unknown. This study takes clonal evolution to the spatial level by describing a novel technique examining the spatial location of mutated clones in the bone marrow and the first evidence that mutated hematopoietic clones are spatially constrained and have heterogenous locations within millimeters of distance. See related article by Young et al., p. 153 (10).","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676842","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}
L. Meriranta, Selma Sorri, K. Huse, Xiaonan Liu, I. Spasevska, Sadia Zafar, Iftekhar Chowdhury, O. Dufva, Eerika Sahlberg, Luka Tandaric, M. Karjalainen-Lindsberg, Marko Hyytiainen, M. Varjosalo, J. Myklebust, S. Leppa
{"title":"Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-cell Lymphoma.","authors":"L. Meriranta, Selma Sorri, K. Huse, Xiaonan Liu, I. Spasevska, Sadia Zafar, Iftekhar Chowdhury, O. Dufva, Eerika Sahlberg, Luka Tandaric, M. Karjalainen-Lindsberg, Marko Hyytiainen, M. Varjosalo, J. Myklebust, S. Leppa","doi":"10.1158/2643-3230.BCD-23-0182","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-23-0182","url":null,"abstract":"Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL), are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin-ligase (CRL) with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiological KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the BTB domain of KLHL6 disrupted its localization and heterodimerization, and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140693421","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}
{"title":"Q&A: Owen Witte on Translational Research in Cancer.","authors":"","doi":"10.1158/2643-3230.BCD-24-0069","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0069","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855845","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}
{"title":"Q&A: Owen Witte on Leukemia Genetics.","authors":"David Gennert","doi":"10.1158/2643-3230.BCD-24-0069","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0069","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140733373","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}
Abou A Koundio, M. Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Touré, Martine Raphael
{"title":"Abstract P36: BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES","authors":"Abou A Koundio, M. Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Touré, Martine Raphael","doi":"10.1158/2643-3249.bcdsymp24-p36","DOIUrl":"https://doi.org/10.1158/2643-3249.bcdsymp24-p36","url":null,"abstract":"\u0000 OBJECTIVE: ALL is the most common cancer in children and the most common cause of cancer death before the age of 20. In low- and middle-income countries, ALL is associated with poor outcomes. Many constraints are at the root of management failures. Therefore, in view of the progressive improvements in the efficacy of chemotherapeutic regimens, we deemed it necessary to conduct this study, the objective of which is to evaluate the role of biology in the management of children with ALL in the Oncopediatric Unit of Dakar. METHODS: This is a prospective analytical study that started on November 15th, 2021 at the UOP in collaboration with the hematology and immunology laboratories. All newly diagnosed patients with ALL based-on cytology and/or immunophenotyping, treated according to the ALL-GFAOP protocol and registered in the REDcap database are included. RESULTS: From November, 15th 2021 to July, 31th 2023, 48 patients were diagnosed with de novo ALL. With an average age of 7.8 years, female represented the main group (52,08%). According to immunophenotyping, the B profile was found in 25.0 % and the T profile in 22.9 %. The ALL T group was older (9.2 vs 4.4 years) and have had higher platelet counts (122272.7 vs 46916.7) at diagnosis than the ALL B group. This latter had higher hemoglobin (7.4 vs 6.8), white blood cell (127296.2 vs 56511.2) and blast counts at diagnosis in peripheral blood (69.4% vs 55.1%) and also in bone marrow (84.2% vs 72.5%) and higher rate of residual blast counts at Day8 after induction (9198.4 vs 1301.4). Regarding corticosensitivity at D8 of induction, no difference was found according to the number of blasts, the hemoglobinlevel and the immunological profile at diagnosis. However, patients with hyperleukocytic ALL with a relatively higher platelet count were more sensitive to corticosteroid therapy. CONCLUSIONS: Understanding the biology of acute ALL is of major interest in the effectiveness of therapeutic approaches to this type of hematology malignancies.\u0000 Citation Format: Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael. BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P36.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140266375","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}
S. Chaudhry, Felipe Beckedorff, S. Jasdanwala, T. Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, S. Montoya, Daniel Bilbao, J. Afaghani, Josean Rodriguez, Shruti Bhatt, Eric Wang, Justin Taylor
{"title":"Abstract P26: Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS","authors":"S. Chaudhry, Felipe Beckedorff, S. Jasdanwala, T. Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, S. Montoya, Daniel Bilbao, J. Afaghani, Josean Rodriguez, Shruti Bhatt, Eric Wang, Justin Taylor","doi":"10.1158/2643-3249.bcdsymp24-p26","DOIUrl":"https://doi.org/10.1158/2643-3249.bcdsymp24-p26","url":null,"abstract":"\u0000 SF3B1 mutations, the most frequent spliceosomal alterations across cancers, occur in 25% of myelodysplastic syndromes (MDS) patients yet lack effective therapies. Two phase 2 clinical trials with the XPO1 inhibitors in high-risk MDS revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs) out of the nucleus. Given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome, we hypothesized that XPO1 inhibition may preferentially affect SF3B1-mutant cells and that SF3B1-mutant high-risk MDS patients would have a better response to rational targeted drug combinations with XPO1 inhibitors. To evaluate the mechanism underlying the preferential sensitivity of SF3B1-mutant cells to XPO1 inhibition, we conducted subcellular RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and mutant cells. Transcriptomic analysis revealed increased global retention of RNA transcripts and elevated snRNAs in the nucleus after XPO1 inhibition in the SF3B1 mutant cell line. Global RNA expression and splicing analysis revealed increased alternative splicing in SF3B1 mutant cells after XPO1 inhibition. These results suggest that the preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through increased nuclear retention of spliceosomal snRNAs and select mRNAs that results in perturbation of apoptotic pathways. Despite the promising efficacy of XPO1 inhibition in SF3B1-mutated MDS, dose escalation is limited by toxicity. In order to identify novel drug combination targets with lower XPO1 inhibitor doses, we employed whole genome CRISPR screens in two acute myeloid leukemia (AML) cell lines treated with XPO1 inhibitor. We identified two drug targets that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and A1331852 (a BCL-XL inhibitor). In addition, BH3 profiling demonstrated increased priming of the BCL2 and BCL-XL in SF3B1 mutant cells. We further validated these combinations in vivo using competitive transplant assays in Sf3b1 K700E conditional knock-in mice. The combination of eltanexor with venetoclax and eltanexor with A1331852 showed a significant decrease in the Sf3b1-mutant burden in the peripheral blood and bone marrow progenitor compartments, suggesting a preferential sensitivity of the combinations for SF3B1 mutant cells. Although A1331852 exhibited similar results to venetoclax, there was increased weight loss and decrease in hemoglobin associated with BCLXL inhibition. In conclusion, our study provides insight on the mechanisms underlying the heightened sensitivity of XPO1 inhibition in SF3B1-mutant MDS/AML. The identification of BCL2 and BCL-XL as synergistic targets with XPO1 inhibitors, validated by in vivo testing, BH3 profiling, and RNA sequencing, highlights the potential for therapeutic combinations. Speci","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140266927","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}
Shih-Chun Alec Chu, Yi-Wan Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Y. Geffen, Gilbert Omenn, Chandan Kumar, S. Dhanasekaran, Fengchao Yu, E. Traer, J. Tyner, Hui Zhang, Tao Liu, Sara J. C. Gosline, Bing Zhang, A. Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik
{"title":"Abstract P27: Proteogenomic and metabolomic analysis of acute myeloid leukemia reveals molecular and functional underpinnings of cellular and clinical phenotypes","authors":"Shih-Chun Alec Chu, Yi-Wan Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Y. Geffen, Gilbert Omenn, Chandan Kumar, S. Dhanasekaran, Fengchao Yu, E. Traer, J. Tyner, Hui Zhang, Tao Liu, Sara J. C. Gosline, Bing Zhang, A. Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik","doi":"10.1158/2643-3249.bcdsymp24-p27","DOIUrl":"https://doi.org/10.1158/2643-3249.bcdsymp24-p27","url":null,"abstract":"\u0000 Acute myeloid leukemia (AML) is a blood malignancy of poor prognosis with marked heterogeneity. To elucidate the underlying mechanisms that drive AML as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) effort, we performed large scale comprehensive genomics, transcriptomics, proteomics including multiple post-translational modifications (phosphorylation, acetylation, and glycosylation), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. Applying the similarity network fusion method on both transcriptomics and proteomics data, we identified 8 proteogenomic clusters. These clusters recapitulate specific recurrent mutations, fusions, structural variants, and established clinical subtypes available within the cohort, as well as reveal new cluster-specific phenotypes within other multi-omic datasets. We used single-cell RNAseq data as a reference to perform immune component analysis for collected bulk samples. The result reveals that our proteogenomic clustering also captures the variations of AML differentiation hierarchies including CD14+ monocyte-like and GMP-like AML. To assess the complex disease nature of AML, we performed functional analysis for each cluster to reveal interplay between multiple genomic aberrations such as NPM1, FLT3-ITD, DNMT3A mutations, complex chromosomal alterations, and the leukemia cell differentiation. Additionally, the multi-omics analysis performed not only connects previously identified molecular drivers and cell differentiation variations within AML, but also links them with observed cancer metabolomic reprogramming alongside differences in MTOR signaling, MYC activities, mitochondrial activities, and drug responses. Moreover, our study also identified site-specific post-translational modifications previously not known in AML, highlighting the valuable insights and clinical relevance of these newly identified clusters.\u0000 Citation Format: Shih-Chun Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Yifat Geffen, Gilbert Omenn, Chandan Kumar, Saravana Dhanasekaran, Fengchao Yu, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I Nesvizhskii, Marcin Cieslik. Proteogenomic and metabolomic analysis of acute myeloid leukemia reveals molecular and functional underpinnings of cellular and clinical phenotypes [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P27.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140080771","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}