Causal Linkage of Presence of Mutant NPM1 to Efficacy of Novel Therapeutic Agents Against Aml Cells With Mutant NPM1

Authors

Christopher P Mill
Warren Fiskus
Kaberi Das
John A Davis
Christine E Birdwell
Tapan M Kadia
Courtney D DiNardo
Naval Daver
Koichi Takahashi
Koji Sasaki
Gerard M McGeehan
Xinjia Ruan
Xiaoping Su
Sanam Loghavi
Hagop Kantarjian
Kapil N Bhalla

Language

English

Publication Date

6-1-2023

Journal

Leukemia

DOI

10.1038/s41375-023-01882-4

PMID

36977823

PMCID

PMC10244173

PubMedCentral® Posted Date

3-28-2023

PubMedCentral® Full Text Version

Post-print

Abstract

In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.

Keywords

Humans, Aged, Nuclear Proteins, Nucleophosmin, Panobinostat, Neoplasm Recurrence, Local, Mutation, Cytarabine, Leukemia, Myeloid, Acute, fms-Like Tyrosine Kinase 3, Targeted therapies, Acute myeloid leukaemia

Published Open-Access

yes

Recommended Citation

Mill, Christopher P; Fiskus, Warren; Das, Kaberi; et al., "Causal Linkage of Presence of Mutant NPM1 to Efficacy of Novel Therapeutic Agents Against Aml Cells With Mutant NPM1" (2023). Faculty, Staff and Student Publications. 5552.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5552