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

Language

English

Publication Date

2-6-2025

Journal

Blood

DOI

10.1182/blood.2024026388

PMID

39561280

PMCID

PMC11811934

PubMedCentral® Posted Date

11-22-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Animals, Leukemia, Myeloid, Acute, Mice, Myeloproliferative Disorders, Cyclin-Dependent Kinase-Activating Kinase, Cyclin-Dependent Kinases, Protein Kinase Inhibitors, Pyrazoles, Cell Transformation, Neoplastic, Nitriles, Xenograft Model Antitumor Assays, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Pyrimidines

Published Open-Access

yes

Recommended Citation

Fiskus, Warren; Mill, Christopher P; Bose, Prithviraj; et al., "Preclinical Efficacy of CDK7 Inhibitor-Based Combinations Against Myeloproliferative Neoplasms Transformed to AML" (2025). Faculty, Staff and Student Publications. 5570.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5570