Reference Detail

Ref Type

Journal Article

PMID

(29977015)

Authors

Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia			2018 Jul 05	75-87	Leukemia

URL

Abstract Text

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 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 (3-5-fold lower IC50) for ibrutinib-based chemical inhibition of Btk. Primary murine progenitor cells from G-CSFR-Q741x knock-in mice validated activation of Btk by the mutant receptor and retrovirally transduced human CD34+ umbilical cord blood cells expressing mutant receptors displayed enhanced sensitivity to Ibrutinib. A significantly lower clonogenic potential was displayed by both murine and human primary cells expressing mutated receptors upon ibrutinib treatment. Finally, a dramatic synergy was observed between ibrutinib and ruxolinitib at lower dose of the individual drug. Altogether, 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. Phospho-tyrosine data are available via ProteomeXchange with identifier PXD009662.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CSF3R T618I	Advanced Solid Tumor	sensitive	Ibrutinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing CSF3R T618I were sensitive to treatment with Imbruvica (ibrutinib) in culture, demonstrating a reduced cell proliferation (PMID: 29977015).	29977015
CSF3R T618I	Advanced Solid Tumor	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) reduced colony formation of cells expressing CSF3R T618I in culture (PMID: 26475333, PMID: 29977015).	26475333 29977015
CSF3R Q741*	Advanced Solid Tumor	sensitive	Ibrutinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing CSF3R Q741* were sensitive to treatment with Imbruvica (ibrutinib) in culture, demonstrating a reduced cell proliferation (PMID: 29977015).	29977015
CSF3R T618I	Advanced Solid Tumor	sensitive	Ibrutinib + Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Imbruvica (ibrutinib) and Jakafi (ruxolitinib) resulted in a synergistic effect in cells expressing CSF3R T618I, demonstrating greater decreased cell viability as compared to either agent alone (PMID: 29977015).	29977015
CSF3R Q741*	Advanced Solid Tumor	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing CSF3R Q741* were sensitive to treatment with Jakafi (ruxolitinib) in culture, demonstrating decreased total colony formation (PMID: 29977015).	29977015
CSF3R Q741*	Advanced Solid Tumor	sensitive	Ibrutinib + Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Imbruvica (ibrutinib) and Jakafi (ruxolitinib) resulted in a synergistic effect in cells expressing CSF3R Q741*, demonstrating greater decreased cell viability as compared to either agent alone (PMID: 29977015).	29977015