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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
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
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
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, Feb 2026).
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, Feb 2026).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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
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 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 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