Preclinical efficacy of CDK7 inhibitor–based combinations against myeloproliferative neoplasms transformed to AML Journal Article
| Authors: | Fiskus, W.; Mill, C. P.; Bose, P.; Masarova, L.; Pemmaraju, N.; Dunbar, A.; Birdwell, C. E.; Davis, J. A.; Das, K.; Hou, H.; Manshouri, T.; Jain, A.; Malovannaya, A.; Philip, K.; Alhamadani, N.; Matthews, A.; Lin, K.; Flores, L. B.; Loghavi, S.; DiNardo, C.; Su, X.; Rampal, R. K.; Bhalla, K. N. |
| Article Title: | 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. © 2025 American Society of Hematology |
| Keywords: | controlled study; myeloproliferative disorders; unclassified drug; human cell; genetics; myeloproliferative disorder; leukemia, myeloid, acute; drug efficacy; nonhuman; antineoplastic agent; mass spectrometry; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cell viability; gene expression; protein kinase inhibitor; antineoplastic combined chemotherapy protocols; animal experiment; cohort analysis; caspase 3; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; pyrimidines; cell transformation, neoplastic; protein kinase inhibitors; pyrazole derivative; pyrazoles; cd11b antigen; myc protein; tumor cell line; caspase 9; drug therapy; pyrimidine derivative; cyclin dependent kinase inhibitor; protein p21; oncogene c myb; myeloproliferative neoplasm; cyclin dependent kinase 7; cyclin dependent kinase 6; acute myeloid leukemia; protein kinase pim 1; protein myb; cytometry; protein bad; ruxolitinib; humans; human; article; rna sequencing; clustered regularly interspaced short palindromic repeat; birabresib; pelabresib; neoplastic cell transformation; oclacitinib; gne 049; sy 5609; hel cell line (erythroid leukemia) |
| Journal Title: | Blood |
| Volume: | 145 |
| Issue: | 6 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2025-02-06 |
| Start Page: | 612 |
| End Page: | 624 |
| Language: | English |
| DOI: | 10.1182/blood.2024026388 |
| PUBMED: | 39561280 |
| PROVIDER: | scopus |
| PMCID: | PMC11811934 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
