CD135

Fms-related tyrosine kinase 3
Identifiers
Symbols	FLT3 ; STK1; CD135; FLK2
External IDs	Template:OMIM5 Template:MGI HomoloGene: 3040
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Cellular component Template:GNF GO Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

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List of terms related to CD135

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

CD135 is a cytokine receptor expressed on the surface of hematopoietic progenitor cells.

Synonyms

fms-like tyrosine kinase receptor-3 (Flt3), fetal liver kinase-2 (Flk2)

Cell Surface Marker

Cluster of differentiation (CD) molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrow. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) expresse high surface levels of CD135. This marker is therefore used to differentiate hematopoietic stem cells (HSC), which are CD135 negative, from MPPs, which are CD135 positive.

Ligand

CD135 is the receptor for the cytokine Flt3 ligand (Flt3L).

Function

CD135 (AKA FMS-like tyrosine kinase 3; FLT3) is a receptor tyrosine kinase type III. When this receptor binds to Flt3L it forms a dimer with itself (homodimer) which activates signaling through second messengers. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development, but not for the development of other blood cells (myeloid development).

Role in cancer

CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer.

Acute Myelocytic Leukemia with a normal karyotype (CN-AML) represents a cytogenetic group with an intermediate prognosis but a substantial molecular and clinical heterogenecity. Within this subgroup the presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutations predicts a less favorable outcome. (DNA microassays are used to profile gene expression).

FLT3 expression was higher in AML and acute B-ALL than in CML and acute T-ALL. FLT3 expression in the blast phase is greater than in the accelerated phase. FLT3 mRNA is expressed in all patients with B-ALL and AML and 90% of patients with T-ALL. FLT3 m RNA varies widely among patients with wt-FLT3 and patients with the highest wt-FLT3 have a significantly increased risk of relapse and death. The blasts involved also have exquisite and selective sensitivity to FLT3 inhibition in-vitro. High wt-FLT3 is indistinguishable from FLT3ITD as a poor prognostic indicator.

FLT3 presents in 20-30% of de novo AML. Typically patients have normal cytogenetics, leukocytosis and monocytic differentiation. An FLT3 "activation loop" mutation is present at D835 and is associated with AML. FLT3 didn't correlate with the FAB subtype. Complete responses to therapy weren't different between patients with and without FLT3 but a +FLT3 had a higher relapse rate and decreased overall survival. A lack of effect of FLT3ITD mutation on the complete response rate might be explained by the lack of effect of the FLT3ITD mutation on chemosensitivity. An analysis of the FLT3ITD allelic ratio has prognostic capacity. A low ratio (<0.2) denotes more responsiveness; a high ratio (>0.78) means a low response and increased risk of relapse.

Among the most common mutations found in cytogenetically normal (CN-AML) are those of the FMS-like tyrosine kinase 3 (FLT3) genes, namely, FLT3-internal tandem duplications (of the juxtamembrane region; ITD) and FLT3 tyrosine kinase domain (point) mutations (TKD). Both of these mutations induce change in the FLT3, which is a gene that encodes for a tyrosine kinase receptor. FLT3ITD induced aberrant signaling includes the strong activation of a signal transducer and activator of transcription 5 (STAT5). FLT3TKD cannot induce or activate STAT5 target genes. When the gene is mutated its mechanism is similar to that of a mutated KIT; it activates the abnormal mechanism of myeloblast proliferation and survival. FLT3ITD is an independent prognostic factor and probably one of the most important molecular prognostic markers in AML, particularly in CN-AML. The incidence of FLT3TKD is much less (~5-6%) in CN-AML.

See also

• Cluster of differentiation
• cytokine receptor
• receptor tyrosine kinase
• tyrosine kinase
• oncogene
• hematopoiesis

Further reading

• Reilly JT (2003). "FLT3 and its role in the pathogenesis of acute myeloid leukaemia". Leuk. Lymphoma. 44 (1): 1–7. PMID 12691136.
• Kottaridis PD, Gale RE, Linch DC (2003). "Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia". Leuk. Lymphoma. 44 (6): 905–13. PMID 12854887.CS1 maint: Multiple names: authors list (link)
• Gilliland DG (2004). "FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors". Best practice & research. Clinical haematology. 16 (3): 409–17. PMID 12935959.
• Drexler HG, Quentmeier H (2005). "FLT3: receptor and ligand". Growth Factors. 22 (2): 71–3. PMID 15253381.
• Naoe T, Kiyoi H (2005). "Normal and oncogenic FLT3". Cell. Mol. Life Sci. 61 (23): 2932–8. doi:10.1007/s00018-004-4274-x. PMID 15583855.
• Sternberg DW, Licht JD (2005). "Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges". Curr. Opin. Hematol. 12 (1): 7–13. PMID 15604885.
• Marcucci G, Mrózek K, Bloomfield CD (2005). "Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics". Curr. Opin. Hematol. 12 (1): 68–75. PMID 15604894.CS1 maint: Multiple names: authors list (link)
• Markovic A, MacKenzie KL, Lock RB (2005). "FLT-3: a new focus in the understanding of acute leukemia". Int. J. Biochem. Cell Biol. 37 (6): 1168–72. doi:10.1016/j.biocel.2004.12.005. PMID 15778081.CS1 maint: Multiple names: authors list (link)
• Zheng R, Small D (2006). "Mutant FLT3 signaling contributes to a block in myeloid differentiation". Leuk. Lymphoma. 46 (12): 1679–87. doi:10.1080/10428190500261740. PMID 16263569.
• Parcells BW, Ikeda AK, Simms-Waldrip T; et al. (2007). "FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia". Stem Cells. 24 (5): 1174–84. doi:10.1634/stemcells.2005-0519. PMID 16410383.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Stubbs MC, Armstrong SA (2007). "FLT3 as a therapeutic target in childhood acute leukemia". Current drug targets. 8 (6): 703–14. PMID 17584026.

External links

• CD135+Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)

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