Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Theodore P. Braun, Cody Coblentz, Brittany M. Smith, Daniel J. Coleman, Zachary Schonrock, Sarah A. Carratt, Rowan L. Callahan, Breanna Maniaci, Brian J. Druker, Julia E. Maxson

Research output: Contribution to journalArticle

Abstract

Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

Original languageEnglish (US)
Pages (from-to)13670-13679
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number24
DOIs
StatePublished - Jun 16 2020

Keywords

  • Acute myeloid leukemia
  • CSF3R
  • Epigenetics
  • LSD1
  • Targeted

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia'. Together they form a unique fingerprint.

  • Cite this