FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome

Tianxiang Hu, Qing Wu, Yating Chong, Haiyan Qin, Candace J. Poole, Jan Van Riggelen, Mingqiang Ren, John Kenneth Cowell

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Oncogenic transformation of hematopoietic stem cells by chimeric fusion kinases causing constitutive activation of FGFR1 leads to a stem cell leukemia/lymphoma (SCLL) syndrome, accompanied by widespread dysregulation of gene activity. We now show that FGFR1 activation is associated with upregulation of MYC and pharmacological suppression of FGFR1 activation leads to downregulation of MYC and suppression of MYC target genes. Luciferase reporter assays demonstrate that FGFR1 can directly regulate MYC expression and this effect is enhanced in the presence of chimeric FGFR1 kinases. In SCLL cells, a truncated form of FGFR1 is generated by granzyme B cleavage of the chimeric kinases, producing a nucleus-restricted derivative that can bind MYC regulatory regions. Mutation of the granzyme B cleavage site prevents relocation to the nucleus but does not suppress MYC activation, suggesting additional mechanisms of MYC activation in the presence of cytoplasm-restricted chimeric kinases. We show that one of these mechanisms involves activating cytoplasmic STAT5, which upregulates MYC independent of the truncated FGFR1 kinase. Targeting MYC function using shRNA knockdown and 10054-F8 in SCLL cells leads to inhibition of cell proliferation and synergizes with the BGJ398 FGFR1 inhibitor, suggesting a combination therapy that could be used in the treatment of SCLL.

Original languageEnglish (US)
Pages (from-to)2363-2373
Number of pages11
JournalLeukemia
Volume32
Issue number11
DOIs
StatePublished - Nov 1 2018

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Lymphoma
Leukemia
Phosphotransferases
Stem Cells
Granzymes
Up-Regulation
Cell Fusion
Nucleic Acid Regulatory Sequences
Hematopoietic Stem Cells
Luciferases
Small Interfering RNA
Genes
Cytoplasm
Down-Regulation
Cell Proliferation
Pharmacology
Mutation
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome. / Hu, Tianxiang; Wu, Qing; Chong, Yating; Qin, Haiyan; Poole, Candace J.; Van Riggelen, Jan; Ren, Mingqiang; Cowell, John Kenneth.

In: Leukemia, Vol. 32, No. 11, 01.11.2018, p. 2363-2373.

Research output: Contribution to journalArticle

Hu, Tianxiang ; Wu, Qing ; Chong, Yating ; Qin, Haiyan ; Poole, Candace J. ; Van Riggelen, Jan ; Ren, Mingqiang ; Cowell, John Kenneth. / FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome. In: Leukemia. 2018 ; Vol. 32, No. 11. pp. 2363-2373.
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