PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia

Brittany M. Curtiss, Jake VanCampen, Jommel Macaraeg, Garth L. Kong, Akram Taherinasab, Mitsuhiro Tsuchiya, William M. Yashar, Yiu H. Tsang, Wesley Horton, Daniel J. Coleman, Joseph Estabrook, Theresa A. Lusardi, Gordon B. Mills, Brian J. Druker, Julia E. Maxson, Theodore P. Braun

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Responses to kinase-inhibitor therapy in AML are frequently short-lived due to the rapid development of resistance, limiting the clinical efficacy. Combination therapy may improve initial therapeutic responses by targeting pathways used by leukemia cells to escape monotherapy. Here we report that combined inhibition of KIT and lysine-specific demethylase 1 (LSD1) produces synergistic cell death in KIT-mutant AML cell lines and primary patient samples. This drug combination evicts both MYC and PU.1 from chromatin driving cell cycle exit. Using a live cell biosensor for AKT activity, we identify early adaptive changes in kinase signaling following KIT inhibition that are reversed with the addition of LSD1 inhibitor via modulation of the GSK3a/b axis. Multi-omic analyses, including scRNA-seq, ATAC-seq and CUT&Tag, confirm these mechanisms in primary KIT-mutant AML. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.

Original languageEnglish (US)
Pages (from-to)1781-1793
Number of pages13
JournalLeukemia
Volume36
Issue number7
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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