Mutated SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Sarah A. Carratt, Garth L. Kong, Brittany M. Curtiss, Zachary Schonrock, Lauren Maloney, Breanna N. Maniaci, Hunter Z. Blaylock, Adrian Baris, Brian J. Druker, Theodore P. Braun, Julia E. Maxson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of patients with CNL also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutated leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutated hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs, most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by LSD1 inhibitors. In summary, we found that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutated CSF3R through the upregulation of Myc-associated gene expression programs.

Original languageEnglish (US)
Pages (from-to)644-658
Number of pages15
JournalBlood
Volume140
Issue number6
DOIs
StatePublished - Aug 11 2022

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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