Blood Cancer Discovery最新文献

{"title":"Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia.","authors":"Andriana G Kotini, Saul Carcamo, Nataly Cruz-Rodriguez, Malgorzata Olszewska, Tiansu Wang, Deniz Demircioglu, Chan-Jung Chang, Elsa Bernard, Mark P Chao, Ravindra Majeti, Hanzhi Luo, Michael G Kharas, Dan Hasson, Eirini P Papapetrou","doi":"10.1158/2643-3230.BCD-22-0167","DOIUrl":"10.1158/2643-3230.BCD-22-0167","url":null,"abstract":"<p><p>The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.</p><p><strong>Significance: </strong>We report the generation of patient-derived iPSC models of all major genetic groups of human AML. These exhibit phenotypic hallmarks of AML in vitro and in vivo, inform the clonal hierarchy and clonal dynamics of human AML, and exhibit striking similarity to patient-matched primary leukemias upon xenotransplantation. See related commentary by Doulatov, p. 252. This article is highlighted in the In This Issue feature, p. 247.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"4 4","pages":"318-335"},"PeriodicalIF":11.5,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9790582","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":"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":"4 4","pages":"252-253"},"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":"4 4","pages":"294-317"},"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":"4 4","pages":"248-251"},"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":"4 4","pages":"254-266"},"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":"4 4","pages":"267-275"},"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":"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}

{"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":"4 3","pages":"176-179"},"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 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":" ","pages":""},"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 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 &gt;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}