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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 Leukemia
Vol
Issue
Date 2018 Jul 05
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 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
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 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 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 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