Efficacy of Novel Agents Against Cellular Models of Familial Platelet Disorder With Myeloid Malignancy (FPD-MM)

Authors

Christopher P Mill
Warren C Fiskus
Courtney D DiNardo
Patrick Reville
John A Davis
Christine E Birdwell
Kaberi Das
Hanxi Hou
Koichi Takahashi
Lauren Flores
Xinjia Ruan
Xiaoping Su
Sanam Loghavi
Joseph D Khoury
Kapil N Bhalla

Language

English

Publication Date

2-5-2024

Journal

Blood Cancer Journal

DOI

10.1038/s41408-024-00981-4

PMID

38316746

PMCID

PMC10844204

PubMedCentral® Posted Date

2-5-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

Keywords

Humans, Animals, Mice, Core Binding Factor Alpha 2 Subunit, Leukemia, Myeloid, Acute, Homoharringtonine, Blood Platelets, Blood Platelet Disorders, Proto-Oncogene Proteins c-bcl-2, Targeted therapies, Acute myeloid leukaemia

Published Open-Access

yes

Recommended Citation

Mill, Christopher P; Fiskus, Warren C; DiNardo, Courtney D; et al., "Efficacy of Novel Agents Against Cellular Models of Familial Platelet Disorder With Myeloid Malignancy (FPD-MM)" (2024). Faculty, Staff and Student Publications. 5554.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5554