A novel KIT mutation results in piebaldism with progressive depigmentation

Richards, Kristen A.; Fukai, Kazuyoshi; Oiso, Naoki; Paller, Amy S.

doi:10.1067/mjd.2001.112221

Cited by 84 publications

(52 citation statements)

References 27 publications

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“…This is supported by the observation that human mutations in the encoded tyrosine kinase region of KIT have been shown to cause piebaldism, an autosomal dominant disorder characterized by white hair and hypopigmented skin patches on the forehead, torso, and extremities. 6,7 In addition, murine models with human xenograft skin were subjected to KIT inhibitory antibody (K44.2), which led to melanocyte loss and a decrease in differentiation antigens and melanocyte dendritic processes. Prolonged KIT inhibition led to melanocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Imatinib mesylate causes hypopigmentation in the skin

Tsao

Kantarjian

Cortes

et al. 2003

Cancer

140

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BACKGROUNDImatinib mesylate is a tyrosine kinase inhibitor that targets the BCR‐ABL protein in CML, c‐kit (KIT) and platelet‐derived growth factor receptors. In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented.METHODSIn this case series, the authors describe unique clinical findings of skin hypopigmentation in six patients with CML who were treated with imatinib mesylate.RESULTSMost patients developed onset of skin hypopigmentation within the first month of treatment and all of the patients experienced additional drug toxicity. Despite patient susceptibility to toxicity, the presence of hypopigmentation did not appear to predict leukemic cell response or clinical outcome. All six patients established a hematologic response but only two patients had a complete cytogenetic response. Imatinib mesylate induced hypopigmentation also appeared to be reversible and potentially dose related.CONCLUSIONSkin hypopigmentation is a benign side effect from imatinib mesylate treatment that appears to be reversible upon discontinuation or dose reduction. Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk‐2). Microphthalmia (Mi), a basic helix‐loop‐helix leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production. Cancer 2003. © 2003 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Imatinib mesylate causes hypopigmentation in the skin

Tsao

Kantarjian

Cortes

et al. 2003

Cancer

140

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“…Specifically, gene duplication and splice mutations in W are responsible for the white coat color in Large White pigs, whereas an inversion mutation in W presents the Rump White color pattern in mice (Stephenson et al, 1994;Marklund et al, 1998). Similarly, piebaldism, a rare human autosomal dominant disorder of melanocyte development, has been traced to a number of point, deletion, splice, and insertion mutations in the W locus (Richards et al, 2001).…”

mentioning

confidence: 99%

Hair Depigmentation Is a Biological Readout for Pharmacological Inhibition of KIT in Mice and Humans

Moss¹,

Toner²,

Cherrington³

et al. 2003

J Pharmacol Exp Ther

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Deregulated activation of the KIT receptor tyrosine kinase has been implicated in several human cancers and in inflammation, making it an attractive target for therapeutic intervention. Conversely, deficiencies in KIT signaling have been implicated in human and animal hair pigmentation disorders, reflecting a role for KIT in the development and function of melanocytes. The goal of this study was to explore the potential utility of hair depigmentation as a biological readout for systemic inhibition of KIT by SU11248 5-, an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptors, vascular endothelial growth factor receptors, KIT, and FLT3. Oral SU11248 treatment induced dose-dependent depigmentation of newly regrown hair in depilated C57BL/6 mice. Similar effects were seen after administration of a KIT-neutralizing antibody. SU11248-induced hair depigmentation was reversible with cessation of treatment. Histological and immunohistochemical evaluation of mouse skin samples supported these observations and revealed that SU11248 has no effect on levels of KIT-positive melanocytes associated with hair follicles, indicating that the inhibitory effect is at the level of melanocyte function rather than their development/survival. Similar hair depigmentation has been noted in several cancer patients receiving SU11248 in phase I trials. Strikingly, patient scalp hair exhibits bands of depigmentation and pigmentation that correspond, respectively, to periods of treatment and dosing rest periods. These data demonstrate that hair pigmentation can serve as a dose-dependent, dynamic, biological readout for KIT inhibition in mice, and, apparently, in humans.

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“…1987). A variety of studies have reported KIT point mutations and deletions in piebald individuals (Giebel and Spritz, 1991;Fleischman et al, 1991;Fleischman, 1992;Spritz et al, 1992a;Spritz et al, 1992b;Spritz et al, 1993;Ezoe et al, 1995;Riva et al, 1995;Fleischman et al, 1996;Nomura et al, 1998;Richards et al, 2001). Furthermore, we have recently reported three novel mutations in two families and one isolated case (Syrris et al, 2000).…”

Section: Introductionmentioning

confidence: 64%

Human piebaldism: six novel mutations of the proto-oncogene KIT

et al. 2002

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Human piebaldism is a rare autosomal dominant disorder that comprises congenital patchy depigmentation of the scalp, forehead, trunk and limbs. It is caused by mutations in the cellsurface receptor tyrosine kinase gene (KIT, also c-kit). We screened three families and three isolated cases of piebaldism from different countries for mutations in the KIT gene using automated sequencing methods. We report six novel KIT point mutations: three missense (C788R, W835R, P869S) at highly conserved amino acid sites; one nonsense (Q347X) that results in termination of translation of the KIT gene in exon 6; and two splice site nucleotide substitutions (IVS13+2T>G, IVS17-1G>A) that are predicted to impair normal splicing. These mutations were not detected in over 100 normal individuals and are likely to be the cause of piebaldism in our subjects.

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A novel KIT mutation results in piebaldism with progressive depigmentation

Cited by 84 publications

References 27 publications

Imatinib mesylate causes hypopigmentation in the skin

Imatinib mesylate causes hypopigmentation in the skin

Hair Depigmentation Is a Biological Readout for Pharmacological Inhibition of KIT in Mice and Humans

Human piebaldism: six novel mutations of the proto-oncogene KIT

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