Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	31	8	2017 08	1770-1778	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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Showing 1 to 13 of 13 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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 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 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 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	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 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 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 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
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

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