It encodes a membrane- bound glycosylated protein of 993 amino acids using a molecular weight of 158-160 kDa, as well as a non-glycosylated isoform of 130-143 kDa that is definitely not linked together with the plasma membrane [10,12]. After the cloning in the Flt3 gene, soluble mouse Flt3 was utilised to clone the gene encoding the mouse Flt3 ligand (FL) [13]. The mouse FL cDNA was then employed to clone the human FL gene [14]. The mouse and human FL genes encode proteins of 231 and 235 amino acids, respectively [15]. The cytoplasmic domains of murine and human FL present only 52% identity in the cytoplasmic domain. The FL gene encodes a style one transmembrane protein that consists of an amino-terminal signaling peptide, four extracellular helical domains, spacer and tether areas, a transmembrane domain along with a tiny cytoplasmic domain [15]. FL is expressed by most tissues, which include hematopoietic organs (spleen, thymus, peripheral blood and bone marrow) plus the prostate, ovary, kidney, lung, colon, little intestine, testis, heart and placenta, using the highest level of expression in peripheral blood mononuclear cells [11]. The brain is probably the couple of tissues while not demonstrable expression of FL.
Most immortalized hematopoietic cell lines express FL [11,16]. The expression of FL by a wide selection of tissues is in contrast towards the limited expression pattern of FLT3, that is mainly found in early hematopoietic progenitor cells. These observations indicate the expression of FLT3 is really a rate-limiting stage in determining the tissuespecificity of FLT3 signaling pathways. FLT3 mutations in hematopoietic Tivozanib structure malignancies In 1996, Nakao et al. [17] observed a exceptional mutation of FLT3 in AML cells. This mutation, comprising an ITD in the JM domain on the receptor (Figure one), induced the coding sequence for being duplicated and inserted in the direct head-to-tail succession [17]. Subsequent studies showed that ITD mutations on the FLT3 gene come about in about 24% of grownup AML patients [2]. Additionally, activating level mutations of your FLT3 TKD, primarily at aspartic acid 835 (Figure one), are present in approximately 7% of AML sufferers [9].
Due to the fact the primary description, various research have confirmed and extended these findings on the extent that FLT3 mutations are presently essentially the most frequent single mutations identified in AML, and roughly one-third of AML patients have mutations of this gene [1,18]. FLT3-ITD mutations have also been detected in 3% of individuals with myelodysplastic syndromes [1], and occasional sufferers with acute FK-506 lymphoid leukemia [19,20] and continual myeloid leukemia [21]. They’ve not been found in individuals with chronic lymphoid leukemia, non-Hodgkin?s lymphoma or many different myeloma [1], or in standard folks .