Proteomics

Dataset Information

46

Time resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors


ABSTRACT: Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we utilized a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild-type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton’s Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (5-fold lower IC50) for Ibrutinib-based chemical inhibition of Btk. Finally, primary murine progenitor cells from G-CSFR-d715x knock-in mice validate activation of Btk by the mutant receptor, and display enhanced sensitivity to Ibrutinib. Together, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus musculus  

TISSUE(S): Cell Suspension Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Pankaj Dwivedi  

LAB HEAD: Kenneth Greis

PROVIDER: PXD009662 | Pride | 2018-07-11

REPOSITORIES: Pride

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Publications

Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors.

Dwivedi Pankaj P   Muench David E DE   Wagner Michael M   Azam Mohammad M   Grimes H Leighton HL   Greis Kenneth D KD  

Leukemia 20180705 1


Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we used a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF  ...[more]

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