Critical individual roles of the BCR and FGFR1 kinase domains in BCR-FGFR1-driven stem cell leukemia/lymphoma syndrome

Yating Chong, Yun Liu, Sumin Lu, Baohuan Cai, Haiyan Qin, Chang Sheng Chang, Mingqiang Ren, John K. Cowell, Tianxiang Hu

Research output: Contribution to journalArticle

Abstract

Constitutive activation of FGFR1, as a result of diverse chromosome translocations, is the hallmark of stem cell leukemia/lymphoma syndrome. The BCR-FGFR1 variant is unique in that the BCR component contributes a serine–threonine kinase (STK) to the N-terminal end of the chimeric FGFR1 kinase. We have deleted the STK domain and mutated the critical Y177 residue and demonstrate that the transforming activity of these mutated genes is reduced compared to the BCR-FGFR1 parental kinase. In addition, we demonstrate that deletion of the FGFR1 tyrosine kinase domain abrogates transforming ability, which is not compensated for by BCR STK activity. Unbiased screening for proteins that are inactivated as a result of loss of the BCR STK identified activated S6 kinase and SHP2 kinase. Genetic and pharmacological inhibition of SHP2 function in SCLL cells expressing BCR-FGFR1 in vitro leads to reduced viability and increased apoptosis. In vivo treatment of SCLL in mice with SHP099 leads to suppression of leukemogenesis, supporting an important role for SHP2 in FGFR1-driven leukemogenesis. In combination with the BGJ398 FGFR1 inhibitor, cell viability in vitro is further suppressed and acts synergistically with SHP099 in vivo suggesting a potential combined targeted therapy option in this subtype of SCLL disease.

Original languageEnglish (US)
JournalInternational Journal of Cancer
DOIs
StateAccepted/In press - Jan 1 2019

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Lymphoma
Leukemia
Phosphotransferases
Stem Cells
Receptor, Fibroblast Growth Factor, Type 1
Ribosomal Protein S6 Kinases
Cell Survival
Chromosomes
Pharmacology
Apoptosis
Therapeutics
Genes
Proteins

Keywords

  • FGFR1
  • SHP2
  • leukemia
  • serine–threonine kinase
  • tyrosine kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Critical individual roles of the BCR and FGFR1 kinase domains in BCR-FGFR1-driven stem cell leukemia/lymphoma syndrome. / Chong, Yating; Liu, Yun; Lu, Sumin; Cai, Baohuan; Qin, Haiyan; Chang, Chang Sheng; Ren, Mingqiang; Cowell, John K.; Hu, Tianxiang.

In: International Journal of Cancer, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Qin, Haiyan

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AU - Ren, Mingqiang

AU - Cowell, John K.

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