CD135

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.