Reference Detail

Ref Type

Journal Article

PMID

(31768065)

Authors

Durham BH, Lopez Rodrigo E, Picarsic J, Abramson D, Rotemberg V, De Munck S, Pannecoucke E, Lu SX, Pastore A, Yoshimi A, Mandelker D, Ceyhan-Birsoy O, Ulaner GA, Walsh M, Yabe M, Petrova-Drus K, Arcila ME, Ladanyi M, Solit DB, Berger MF, Hyman DM, Lacouture ME, Erickson C, Saganty R, Ki M, Dunkel IJ, Santa-María López V, Mora J, Haroche J, Emile JF, Decaux O, Geissmann F, Savvides SN, Drilon A, Diamond EL, Abdel-Wahab O

Title

Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine	25	12	2019 12	1839-1842	Nat Med

URL

Abstract Text

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
CSF1R	NCBI	BANDDOS\|C-FMS\|CD115\|CSF-1R\|CSFR\|FIM2\|FMS\|GPSC\|HDLS\|HDLS1\|M-CSF-R		CSF1R, colony stimulating factor 1 receptor, is a tyrosine kinase and receptor for CSF1 and IL34, which upon ligand binding activates PI3K-AKT-mTOR, RAS-RAF-MEK-ERK and STAT signaling pathways (PMID: 22186992). CSF1R is expressed by tumor-associated macrophages to induce tumor promotion (PMID: 30065206) and therefore, a number of therapies to block Csf1r are under development (PMID: 28716061), and Csf1r activating mutations have been reported in histiocytic neoplasms (PMID: 31768065).	Oncogene

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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description
CSF1R	W450_E456del	deletion	gain of function	CSF1R W450_E456del results in a deletion of seven amino acids within the Ig-like C2 type domain 5 of the Csf1r protein (UniProt.org). W450_E456del confers a gain of function to the Csf1r protein, resulting in cytokine-independent cell growth and increased Mek/Erk signaling in culture (PMID: 31768065).
CSF1R	Y546_K551del	deletion	gain of function	CSF1R Y546_K551del results in the deletion of six amino acids in the regulatory juxtamembrane domain of the Csf1r protein from amino acids 546 to 551 (UniProt.org). Y546_K551del confers a gain of function to the Csf1r protein, as it leads to increased Mek/Erk signaling in vitro and increased cytokine-independent cell growth in culture (PMID: 31768065).
CSF1R	Y561_I564del	deletion	unknown	CSF1R Y561_I564del results in the deletion of four amino acids in the regulatory juxtamembrane domain of the Csf1r protein from amino acids 561 to 564 (UniProt.org). Y561_I564del has been identified in the scientific literature (PMID: 31768065, PMID: 34978715), but has not been biochemically characterized and therefore, its effect on Csf1r protein function is unknown (PubMed, Jun 2025).
KIT	R888W	missense	unknown	KIT R888W lies within the protein kinase domain of the Kit protein (UniProt.org). R888W has been identified in sequencing studies (PMID: 31768065, PMID: 30393068) but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Jul 2025).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CSF1R W450_E456del	Advanced Solid Tumor	sensitive	Pexidartinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing CSF1R W450_E456del demonstrated sensitivity to treatment with Turalio (pexidartinib) in culture (PMID: 31768065).	31768065
CSF1R W450_E456del	Advanced Solid Tumor	sensitive	BLZ945	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing CSF1R W450_E456del demonstrated sensitivity to treatment with BLZ945 in culture (PMID: 31768065).	31768065
CSF1R Y546_K551del	Advanced Solid Tumor	sensitive	BLZ945	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing CSF1R Y546_K551del demonstrated sensitivity to treatment with BLZ945 in culture (PMID: 31768065).	31768065
CSF1R Y546_K551del	Advanced Solid Tumor	sensitive	Pexidartinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing CSF1R Y546_K551del demonstrated sensitivity to treatment with Turalio (pexidartinib) in culture (PMID: 31768065).	31768065
CSF1R Y561_I564del	Advanced Solid Tumor	sensitive	Pexidartinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing CSF1R Y561_I564del demonstrated sensitivity to treatment with Turalio (pexidartinib) in culture (PMID: 31768065).	31768065
CSF1R Y561_I564del	Advanced Solid Tumor	sensitive	BLZ945	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing CSF1R Y561_I564del demonstrated sensitivity to treatment with BLZ945 in culture (PMID: 31768065).	31768065

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