Warren Fiskus, Christopher P Mill, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Andrew Dunbar, Christine E Birdwell, John A Davis, Kaberi Das, Hanxi Hou, Taghi Manshouri, Antrix Jain, Anna Malovannaya, Kevin Philip, Noor Alhamadani, Alicia Matthews, Katie Lin, Lauren B Flores, Sanam Loghavi, Courtney DiNardo, Xiaoping Su, Raajit K Rampal, Kapil N Bhalla
{"title":"基于 CDK7 抑制剂的联合疗法对转化为急性髓细胞性白血病的骨髓增生性肿瘤的临床前疗效。","authors":"Warren Fiskus, Christopher P Mill, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Andrew Dunbar, Christine E Birdwell, John A Davis, Kaberi Das, Hanxi Hou, Taghi Manshouri, Antrix Jain, Anna Malovannaya, Kevin Philip, Noor Alhamadani, Alicia Matthews, Katie Lin, Lauren B Flores, Sanam Loghavi, Courtney DiNardo, Xiaoping Su, Raajit K Rampal, Kapil N Bhalla","doi":"10.1182/blood.2024026388","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment reduced mRNA expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased expression of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase-9, and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced cell viability of HEL cells. Cytometry by time of flight (CyTOF) analysis of SY-5609-treated PD post-MPN sAML stem/progenitor cells showed reduced c-Myc, CDK6, and PU.1 but increased protein levels of CD11b, p21, and cleaved caspase-3. Cotreatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2, and PD post-MPN sAML cells. A CRISPR screen in sAML cells revealed BRD4, CBP, and p300 as codependencies with CDK7i. Accordingly, cotreatment with SY-5609 and the bromodomain and extra-terminal protein inhibitor (BETi) OTX015 or pelabresib or the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared with each agent alone, cotreatment with SY-5609 and OTX015 reduced sAML burden and improved survival without host toxicity. These findings demonstrate promising preclinical activity of CDK7i-based combinations with BETi or CBP/p300 inhibitor against advanced MPNs, including post-MPN sAML.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"612-624"},"PeriodicalIF":21.0000,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.\",\"authors\":\"Warren Fiskus, Christopher P Mill, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Andrew Dunbar, Christine E Birdwell, John A Davis, Kaberi Das, Hanxi Hou, Taghi Manshouri, Antrix Jain, Anna Malovannaya, Kevin Philip, Noor Alhamadani, Alicia Matthews, Katie Lin, Lauren B Flores, Sanam Loghavi, Courtney DiNardo, Xiaoping Su, Raajit K Rampal, Kapil N Bhalla\",\"doi\":\"10.1182/blood.2024026388\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Abstract: </strong>Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment reduced mRNA expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased expression of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase-9, and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced cell viability of HEL cells. Cytometry by time of flight (CyTOF) analysis of SY-5609-treated PD post-MPN sAML stem/progenitor cells showed reduced c-Myc, CDK6, and PU.1 but increased protein levels of CD11b, p21, and cleaved caspase-3. Cotreatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2, and PD post-MPN sAML cells. A CRISPR screen in sAML cells revealed BRD4, CBP, and p300 as codependencies with CDK7i. Accordingly, cotreatment with SY-5609 and the bromodomain and extra-terminal protein inhibitor (BETi) OTX015 or pelabresib or the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared with each agent alone, cotreatment with SY-5609 and OTX015 reduced sAML burden and improved survival without host toxicity. These findings demonstrate promising preclinical activity of CDK7i-based combinations with BETi or CBP/p300 inhibitor against advanced MPNs, including post-MPN sAML.</p>\",\"PeriodicalId\":9102,\"journal\":{\"name\":\"Blood\",\"volume\":\" \",\"pages\":\"612-624\"},\"PeriodicalIF\":21.0000,\"publicationDate\":\"2025-02-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1182/blood.2024026388\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1182/blood.2024026388","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.
Abstract: Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment reduced mRNA expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased expression of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase-9, and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced cell viability of HEL cells. Cytometry by time of flight (CyTOF) analysis of SY-5609-treated PD post-MPN sAML stem/progenitor cells showed reduced c-Myc, CDK6, and PU.1 but increased protein levels of CD11b, p21, and cleaved caspase-3. Cotreatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2, and PD post-MPN sAML cells. A CRISPR screen in sAML cells revealed BRD4, CBP, and p300 as codependencies with CDK7i. Accordingly, cotreatment with SY-5609 and the bromodomain and extra-terminal protein inhibitor (BETi) OTX015 or pelabresib or the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared with each agent alone, cotreatment with SY-5609 and OTX015 reduced sAML burden and improved survival without host toxicity. These findings demonstrate promising preclinical activity of CDK7i-based combinations with BETi or CBP/p300 inhibitor against advanced MPNs, including post-MPN sAML.
期刊介绍:
Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.