Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor beta chain and KIT V654A

Spector, M. S., Iossifov, I., Kritharis, A., He, C., Kolitz, J. E., Lowe, S. W., Allen, S. L. (June 2012) Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor beta chain and KIT V654A. Leukemia, 26 (6). pp. 1422-1425. ISSN 0887-6924

DOI: 10.1038/leu.2011.354


Mast cells exit the bone marrow as immature multilineage cells that circulate in the blood and subsequently undergo full differentiation upon reaching a target organ (reviewed in Gilfillan and Tkaczyk1). Unlike other hematopoietic cells, differentiated mast cells continue to express KIT, a transmembrane receptor with a bipartite intracellular kinase domain.1 The main ligand of KIT is stem cell factor (also known as KIT ligand), which stimulates mast-cell survival, development, maturation and activation.1 Mast cells also express a high-affinity cell-surface IgE receptor, FcεRI, which recognizes the Fc portion of IgE and is required for mast-cell survival via signaling through LYN and SYK kinases.1 Mast-cell leukemia (MCL) is an aggressive form of systemic mastocytosis characterized by the overproliferation of atypical mast cells, promastocytes and blasts that produce, among other substances, tryptase.2 MCL is often linked to somatically acquired activating mutations in the KIT receptor that result in uncontrolled ligand-independent signaling by KIT and hyperproliferation of mast cells (reviewed in Ustun et al.3). The KIT D816V mutation causes resistance to imatinib therapy.3 Mutations in TET2 and NRAS have also been described in mastocytosis patients and each of them segregates with the KIT D816V mutation,4, 5 suggesting that more than one lesion is required to drive leukemogenesis. In order to identify novel MCL determinants, we utilized two approaches to undertake the first comprehensive study of the DNA changes in an MCL patient. This study was approved by the Institutional Review Boards of the North Shore-LIJ Health System and the Cold Spring Harbor Laboratory. The patient gave written informed consent in accordance with the Declaration of Helsinki.

Item Type: Paper
Uncontrolled Keywords: mastocytosis inhibition activation syk
Subjects: diseases & disorders > cancer
diseases & disorders
Investigative techniques and equipment
Investigative techniques and equipment > assays
diseases & disorders > cancer > cancer types > leukemia
diseases & disorders > cancer > cancer types
Investigative techniques and equipment > whole exome sequencing
Investigative techniques and equipment > assays > whole exome sequencing
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL labs > Iossifov lab
CSHL labs > Lowe lab
CSHL Cancer Center Shared Resources > Animal Services
Depositing User: Matt Covey
Date: June 2012
Date Deposited: 18 Jan 2013 15:41
Last Modified: 29 Oct 2015 19:22
PMCID: PMC3368985
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