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Ref Type | Journal Article | ||||||||||||
PMID | (28031554) | ||||||||||||
Authors | Rohrabaugh S, Kesarwani M, Kincaid Z, Huber E, Leddonne J, Siddiqui Z, Khalifa Y, Komurov K, Grimes HL, Azam M | ||||||||||||
Title | Enhanced MAPK signaling is essential for CSF3R-induced leukemia. | ||||||||||||
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Abstract Text | Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone cannot induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL. |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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CSF3R W791* | hematologic cancer | predicted - resistant | Dasatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R W791* demonstrated resistance to treatment with Sprycel (dasatinib) in culture (PMID: 28031554). | 28031554 |
CSF3R W791* | hematologic cancer | predicted - sensitive | AZD1480 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R W791* were sensitive to treatment with AZD1480 in culture, demonstrating decreased cell survival (PMID: 28031554). | 28031554 |
CSF3R T618I CSF3R Q741* | hematologic cancer | predicted - resistant | Dasatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells co-expressing CSF3R T618I and CSF3R Q741* were resistant to treatment with Sprycel (dasatinib) in culture (PMID: 28031554). | 28031554 |
CSF3R T618I CSF3R W791* | hematologic cancer | predicted - resistant | Dasatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells co-expressing CSF3R T618I and CSF3R W791* were resistant to treatment with Sprycel (dasatinib) in culture (PMID: 28031554). | 28031554 |
CSF3R T618I CSF3R Q741* | hematologic cancer | predicted - resistant | AZD1480 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells co-expressing CSF3R T618I and CSF3R Q741* were resistant to treatment with AZD1480 in culture (PMID: 28031554). | 28031554 |
CSF3R Q741* | hematologic cancer | predicted - sensitive | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R Q741* were sensitive to treatment with Jakafi (ruxolitinib) in culture, demonstrating decreased cell survival (PMID: 28031554). | 28031554 |
CSF3R T618I CSF3R Q741* | hematologic cancer | predicted - resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells co-expressing CSF3R T618I and CSF3R Q741* were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 28031554). | 28031554 |
CSF3R T618I CSF3R W791* | hematologic cancer | predicted - resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells co-expressing CSF3R T618I and CSF3R W791* were resistant to treatment with Jakafi (ruxolitinib) in culture, demonstrating decreased cell survival (PMID: 28031554). | 28031554 |
CSF3R Q741* | hematologic cancer | predicted - resistant | Dasatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R Q741* demonstrated resistance to treatment with Sprycel (dasatinib) in culture (PMID: 28031554). | 28031554 |
CSF3R Q741* | hematologic cancer | predicted - sensitive | AZD1480 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R Q741* were sensitive to treatment with AZD1480 in culture, demonstrating decreased cell survival (PMID: 28031554). | 28031554 |
CSF3R T618I CSF3R W791* | hematologic cancer | predicted - resistant | AZD1480 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells co-expressing CSF3R T618I and CSF3R W791* were resistant to treatment with AZD1480 in culture (PMID: 28031554). | 28031554 |
CSF3R T618I | hematologic cancer | predicted - resistant | Dasatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R T618I demonstrated resistance to treatment with Sprycel (dasatinib) in culture (PMID: 28031554). | 28031554 |
CSF3R W791* | hematologic cancer | predicted - sensitive | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing CSF3R W791* were sensitive to treatment with Jakafi (ruxolitinib) in culture, demonstrating decreased cell survival (PMID: 28031554). | 28031554 |