Blood Cancer Discovery最新文献

{"title":"iPSC Models of Leukemia Come of Age.","authors":"Sergei Doulatov","doi":"10.1158/2643-3230.BCD-23-0041","DOIUrl":"10.1158/2643-3230.BCD-23-0041","url":null,"abstract":"<p><strong>Summary: </strong>In this issue of Blood Cancer Discovery, Kotini and colleagues present a strategy for large-scale reprogramming of primary human acute myeloid leukemias (AML) to induced pluripotent stem cell (iPSC). They show that the hematopoietic differentiation of AML iPSCs gives rise to transplantable leukemias with remarkable molecular similarity to the original patients' AML, providing new models and insights into the disease. See related article by Kotini et al., p. 318 (7) .</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793437","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":"The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma.","authors":"Shima Nakanishi, Jiannong Li, Anders E Berglund, Youngchul Kim, Yonghong Zhang, Ling Zhang, Chunying Yang, Jinming Song, Raghavendra G Mirmira, John L Cleveland","doi":"10.1158/2643-3230.BCD-22-0162","DOIUrl":"10.1158/2643-3230.BCD-22-0162","url":null,"abstract":"<p><p>The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given this, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which posttranslationally modifies the eukaryotic translation factor eIF5A. The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where the loss of eIF5A hypusination abolishes malignant transformation of MYC-overexpressing B cells. Mechanistically, integrating RNA sequencing, ribosome sequencing, and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-S phase cell-cycle progression and DNA replication. This circuit thus controls MYC's proliferative response, and it is also activated across multiple malignancies. These findings suggest the hypusine circuit as a therapeutic target for several human tumor types.</p><p><strong>Significance: </strong>Elevated EIF5A and the polyamine-hypusine circuit are manifest in many malignancies, including MYC-driven tumors, and eIF5A hypusination is necessary for MYC proliferative signaling. Not-ably, this circuit controls an oncogenic translational program essential for the development and maintenance of MYC-driven lymphoma, supporting this axis as a target for cancer prevention and treatment. See related commentary by Wilson and Klein, p. 248. This article is highlighted in the In This Issue feature, p. 247.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9788123","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":"An MYC-Driven Vicious Circuit Is a Targetable Achilles' Heel in Lymphoma.","authors":"Erica B Wilson, Ulf Klein","doi":"10.1158/2643-3230.BCD-23-0053","DOIUrl":"10.1158/2643-3230.BCD-23-0053","url":null,"abstract":"<p><strong>Summary: </strong>In this issue of Blood Cancer Discovery, Nakanishi et al. uncover a critical role for the elevated activity of the translation initiation factor eIF5A in the malignant growth of MYC-driven lymphoma. eIF5A is posttranslationally modified by hypusination through MYC oncoprotein-mediated hyperactivation of the polyamine-hypusine circuit, which may represent a promising therapeutic target because an enzyme of this circuit that is required for hypusinating eIF5A proved to be essential for lymphoma development. See related article by Nakanishi et al., p. 294 (4).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9853800","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":"The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms.","authors":"Juan Carlos Balandrán, Audrey Lasry, Iannis Aifantis","doi":"10.1158/2643-3230.BCD-22-0176","DOIUrl":"10.1158/2643-3230.BCD-22-0176","url":null,"abstract":"<p><p>Myeloid malignancies are devastating hematologic cancers with limited therapeutic options. Inflammation is emerging as a novel driver of myeloid malignancy, with important implications for tumor composition, immune response, therapeutic options, and patient survival. Here, we discuss the role of inflammation in normal and malignant hematopoiesis, from clonal hematopoiesis to full-blown myeloid leukemia. We discuss how inflammation shapes clonal output from hematopoietic stem cells, how inflammation alters the immune microenvironment in the bone marrow, and novel therapies aimed at targeting inflammation in myeloid disease.</p><p><strong>Significance: </strong>Inflammation is emerging as an important factor in myeloid malignancies. Understanding the role of inflammation in myeloid transformation, and the interplay between inflammation and other drivers of leukemogenesis, may yield novel avenues for therapy.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10000381","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":"Microbiota Influences on Hematopoiesis and Blood Cancers: New Horizons?","authors":"Jessica R Galloway-Peña, Christian Jobin","doi":"10.1158/2643-3230.BCD-22-0172","DOIUrl":"10.1158/2643-3230.BCD-22-0172","url":null,"abstract":"<p><p>Hematopoiesis governs the generation of immune cells through the differentiation of hematopoietic stem cells (HSC) into various progenitor cells, a process controlled by intrinsic and extrinsic factors. Among extrinsic factors influencing hematopoiesis is the microbiota, or the collection of microorganisms present in various body sites. The microbiota has a profound impact on host homeostasis by virtue of its ability to release various molecules and structural components, which promote normal organ function. In this review, we will discuss the role of microbiota in influencing hematopoiesis and how disrupting the microbiota/host network could lead to hematologic malignancies, as well as highlight important knowledge gaps to move this field of research forward.</p><p><strong>Significance: </strong>Microbiota dysfunction is associated with many pathologic conditions, including hematologic malignancies. In this review, we discuss the role of microbiota in influencing hematopoiesis and how disrupting the microbiota/host network could lead to hematologic malignancies. Understanding how the microbiota influences hematologic malignancies could have an important therapeutic impact for patients.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9846734","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":"Global Shift in Alternative Splicing and Therapeutic Susceptibilities in Leukemia Driven by METTL3 Overexpression.","authors":"Maxime Janin,&nbsp;Manel Esteller","doi":"10.1158/2643-3230.BCD-23-0035","DOIUrl":"10.1158/2643-3230.BCD-23-0035","url":null,"abstract":"<p><strong>Summary: </strong>Mutations in splicing factors are commonly observed in chronic lymphocytic leukemia (CLL); however, other mechanisms can also contribute to the dysregulation of alternative splicing. One example is the overexpression of the m6A RNA methyltransferase METTL3, that by depositing the epitranscriptomic mark in spliceosome transcripts leads to aberrant splicing, but at the same time creates vulnerability to METTL3 inhibitors. See related article by Wu et al., p. 228 (8) .</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9630410","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":"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":null,"pages":null},"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}

{"title":"Abstract A26: Age and Dose Related Changes to the Bone Marrow Microenvironment after Cytotoxic Conditioning with Busulfan","authors":"J. Spencer, C. Burns, R. Verrinder, Farhad Ghazali, N. Abbasizadeh","doi":"10.1158/2643-3249.aml23-a26","DOIUrl":"https://doi.org/10.1158/2643-3249.aml23-a26","url":null,"abstract":"\u0000 Hematopoietic Cell Transplantation (HCT) is a frequently used treatment for hematologic malignancies such as acute myeloid leukemia, multiple myeloma, lymphoma and non-malignant diseases. Preparative regimens before HCT damage the Bone Marrow (BM) niche, but it is not fully known how the cytotoxic preconditioning, whether High or Low intensity, impacts bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time. In addition, the effect of recipient age on these factors has not been completely described. In this study, we sought to longitudinally investigate bone and BM remodeling after Low and High intensity Busulfan (BU) conditioning with the aim of understanding the role that BM niche alterations play in the recovery of the hematopoietic system after transplantation. Using two-photon intravital microscopy, we visualized bone and BM changes in young and adult mice on days 2, 5, and 42 post-transplantation. Both Low and High intensity conditioning were administered with injections of 40 mg/kg and 80 mg/kg busulfan, respectively. Busulfan is a DNA alkylating drug that in combination with cyclophosphamide is being clinically used to treat leukemia. Mice were then transplanted with 1 × 106 whole BM cells from a C57BL/6-Tg(UBC-GFP) mouse. During live imaging, functionality of the vascular system and hematopoietic recovery were studied. For ex vivo imaging, vascular labeling fluorescent antibodies (Alexafluor 647 conjugated to anti-CD31, CD144, and Sca-1) and calcium binding dyes (dye1; Calcein, Dye2; Alizarin) were administered before intracardiac perfusion. Then long bones were harvested, frozen, and the cortical layer was shaved to enable visualization of the BM. Vascular analysis indicated increased leakage in both Low and High intensity conditioning even after 42 days suggesting delayed endothelial recovery following conditioning. Morphological evaluation of the vascular network revealed a decrease in the frequency and increase in the size and density of the vessels at early timepoints that was partially restored by day 42 in young mice only. Bone remodeling in young mice showed a reduction in the dye1/dye2 ratio at day 5 and a more significant decrease by day 42. In the adult mice, a low ratio was observed in BU-conditioned mice only at day 42 post treatment. To further investigate, we classified the metaphyseal and epiphyseal long bone cavities as deposition type, mixed type, and resorption type based on the ratio of the two dyes. The classification analysis indicates that the reduction in dye1/dye2 ratio in BU-conditioned mice over time is primarily due to an increase in resorption type bone cavities in BU-conditioned mice compared to the control. Although donor HSC engraftment is known to be age and dose dependent, our results indicate that long-term microenvironmental changes in the bone and bone marrow may further impact hematopoietic recovery. Overall, our results demonstrate new aspects of bone remodeling and b","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45682634","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":"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}