Loss of the BCR-FGFR1 GEF domain suppresses RhoA activation and enhances B-lymphomagenesis in mice

Tianxiang Hu, Yating Chong, Sumin Lu, Haiyan Qin, Mingqiang Ren, Natasha Marie Savage, Chang Sheng Chang, John Kenneth Cowell

Research output: Contribution to journalArticle

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Abstract

Transformation of hematopoietic stem cells by the BCR–FGFR1 fusion kinase found in a variant of stem cell leukemia/lymphoma (SCLL) syndrome leads to development of B-lymphomas in syngeneic mice and humans. In this study, we show that the relatively rapid onset of this leukemia is potentially related to oncogenic domains within the BCR component. BCR recruited a guanidine nucleotide exchange factor (GEF) domain to the fusion kinase to facilitate activation of small GTPases such as the Ras homology gene family, member A (RHOA). Deletion of this GEF domain increased leukemogenesis, enhanced cell survival and proliferation, and promoted stem cell expansion and lymph node metastasis. This suggests that, in an SCLL context, the presence of the endogenous GEF motif leads to reduced leukemogenesis. Indeed, loss of the GEF domain suppressed activation of RHOA and PTEN, leading to increased activation of AKT. Loss of the GEF domain enhanced cell proliferation and invasion potential, which was also observed in cells in which RHOA is knocked down, supported by the observation that overexpression of RHOA leads to reduced viability and invasion. In vivo depletion of RHOA in SCLL cells significantly increased disease progression and shortened latency. Collectively, these data show that the BCR GEF domain affects phenotypes associated with progression of SCLL through suppression of RHOA signaling. Significance: RHOA activation is a critical event in the progression of BCR–FGFR1–driven leukemogenesis in stem cell leukemia and lymphoma syndrome and is regulated by the BCR GEF domain.

Original languageEnglish (US)
Pages (from-to)114-124
Number of pages11
JournalCancer Research
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2019

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Guanidine
Nucleotides
Lymphoma
Leukemia
Stem Cells
Phosphotransferases
Cell Proliferation
Monomeric GTP-Binding Proteins
ras Genes
Cell Fusion
Hematopoietic Stem Cells
Disease Progression
Cell Survival
Lymph Nodes
Neoplasm Metastasis
Phenotype

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Loss of the BCR-FGFR1 GEF domain suppresses RhoA activation and enhances B-lymphomagenesis in mice. / Hu, Tianxiang; Chong, Yating; Lu, Sumin; Qin, Haiyan; Ren, Mingqiang; Savage, Natasha Marie; Chang, Chang Sheng; Cowell, John Kenneth.

In: Cancer Research, Vol. 79, No. 1, 01.01.2019, p. 114-124.

Research output: Contribution to journalArticle

Hu, Tianxiang ; Chong, Yating ; Lu, Sumin ; Qin, Haiyan ; Ren, Mingqiang ; Savage, Natasha Marie ; Chang, Chang Sheng ; Cowell, John Kenneth. / Loss of the BCR-FGFR1 GEF domain suppresses RhoA activation and enhances B-lymphomagenesis in mice. In: Cancer Research. 2019 ; Vol. 79, No. 1. pp. 114-124.
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