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14 - FMS-related tyrosine kinase 3
- from Part 2.1 - Molecular pathways underlying carcinogenesis: signal transduction
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- By Soheil Meshinchi, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA,USA, Derek L. Stirewalt, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA,USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 144-161
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- Chapter
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Summary
Introduction
Normal hematopoiesis is carefully regulated by a number of genes that permit the renewal of the pluripotential hematopoietic stem cell, while allowing for the proliferation and differentiation of mature hematopoietic cells. FMS-related tyrosine kinase 3 (FLT3) is one of several critical genes that regulate normal hematopoietic proliferation and differentiation. Over the last decade, three types of FLT3 mutations have been described in acute myeloid leukemia (AML). These FLT3 mutations are quite common in AML, occurring in 25–35% of patients. In addition, FLT3 mutations have also been found in acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and myelodysplasia (MDS). Large studies have established that some types of FLT3 mutation are associated with a very poor prognosis in AML patients, and novel agents directed against FLT3 mutations have been recently developed that hold promise for future targeted therapies for these patients. The purpose of this chapter is to review the biology of the FLT3 receptor and to examine the clinical significance of FLT3 mutations in hematopoietic malignancies.
FLT3 cloning and structure
During the early 1990s, several groups independently cloned murine and human FLT3 (also called fetal liver kinase 2, FLK2)(1–4).The human FLT3 gene resides on chromosome 13q12, encoding a 993 amino-acid protein receptor. The FLT3 receptor is a member of the receptor tyrosine kinase III (RTKIII) family. The RTKIII family members are defined by their similar structure, which consists of five immunoglobulin-like extra-cellular (E) domains, a transmembrane (TM) domain, a juxtamembrane (JM) domain, and two intra-cellular tyrosine kinase domains (TKDs) linked by a kinase insert (KI) domain (Figure 14.1; 5,6). In all, FLT3 has 24 exons. The first exon encodes for the signal sequences (SS), while exons 2–12 encode for the five E domains. Exons 13 and 14 primarily encode for the TM and JM domains, respectively, and the critical two tyrosine kinase domains are encoded by exons 15–17 and 19–22, respectively. Like most RTKIII family members, the TKDs are separated by a KI, which links the two intra-cellular kinase domains (5). The C-terminus (CT) is encoded by the final two exons. The entire coding region spans approximately 100 kilobases (kb), with exons ranging in size from 83–562 base pairs (6).