Cancer

Acute myelogenous leukemias (AML); Myeloid leukemias; Leukemias; Lymphoblastic leukemias; Juvenile myelomonocytic leukemias (JMML); Gastrointestinal stromal tumours (GANT); Myelodysplastic syndromes (MSD); Acute promyelocytic leukemias (APL); Cytogenetically normal Acute myeloid leukemias (AML); Core binding factor Acute myeloid leukemias (AML); Chronic myelomonocytic leukemias (CMML); Tetraploidy; Myeloid sarcomas; Acute myeloid leukemias (AML) with T(6;9)(p23;q34); Chronic myeloproliferative disease (CMPD); 8p11 Myeloproliferative syndrome; Bone marrow cancer; Acute myelomonocytic leukemias (AMML); Acute biphenotypic leukemias (BAL); Precursor T-cell acute lymphoblastic leukemias; Leukemias, acute lymphoblastic 3 (B-ALL); Acute myeloblastic leukemias with maturation; Acute myeloid leukemias (AML) with T(8;21)(q22;q22) Translocation; Acute myeloid leukemias (AML) with abnormal bone marrow eosinophils Inv(16)(p13q22) or T(16;16)(p13;q22); Acute myeloblastic leukemias (AML) without maturation; Leukemias, acute lymphoblastic, somatic; Minimally differentiated acute myeloblastic leukemias (AML)

FLT3 is a known oncoprotein (OP). Cancer-related mutations in human tumours point to a gain of function of the protein kinase. The active form of the protein kinase normally acts to promote tumour cell proliferation. FLT3 is linked with Acute Myeloid Leukemia (AML), which is a rare blood cancer disease which will displace healthy blood cells and can lead to fever, shortness of breath, fatigue, and easy bruising. Myeloid Leukemia is a cancer of the myeloid progenitor cells and it can affect myeloid, bone, and bone marrow. Lymphoblastic Leukemia is related to leukemia and can affect T cells, B cells, and bone tissue. Juvenile Myelomonocytic Leukemia (JMML) is a rare chronic blood leukemia that mostly affects young (under 4 years) children. Myelodysplastic Syndromes (MSD) is a rare bone marrow cancer resulting in insufficient functioning and circulating red blood cells. Acute Promyelocytic Leukemia is also a rare bone marrow cancer. Tetraploidy is a rare chromosomal aberration disorder that is related to leukemia. The rare cancer Myeloid Sarcoma is characterized by an accumulation of white blood cells forming a solid cellular mass. Chronic Myeloproliferative Disease is another rare cancer of the bone marrow which results in impaired red blood cell production. Chronic Myeloproliferative Disease (CMPD) is a slow growing cancer. Acute Biphenotypic Leukemia (BAL) is a rare cancer arising from both the lymphoid and myeloid lineages. BAL is related to the complement cascade and clotting cascade pathways. Precursor T-Cell Acute Lymphoblastic Leukemia is a rare cancer and some of its related pathways include the gefitinib pathway, and the cytokine inflammatory response. Leukemia, Acute Lymphoblastic 3 (B-ALL) is a rare cancer which is related to the gefitinib and the transcription factors in neurogenesis pathways. Acute Myeloblastic Leukemia with Maturation is a sub-type of AML. Acute Myeloblastic Leukemia Without Maturation is a rapidly progressing form of leukemia where white blood cells are overproduced in the bone marrow. Minimally Differentiated Acute Myeloblastic Leukemia is a subtype of AML. Gastrointestinal Stromal tumour (GANT) is a soft tissue sarcoma growing from the stomach, intestines, or rectum. STAT5A activation can be inhibited with a Y589F or Y591F mutation. The Y599F mutation can interrupt FLT3 complex formation with PTPN11/SHP2. FLT3 Kinase phosphotransferase activity can abolished with a K644A mutation.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Brain glioblastomas (%CFC= +357, p<0.057); and Breast epithelial carcinomas (%CFC= +147, p<0.037). The COSMIC website notes an up-regulated expression score for FLT3 in diverse human cancers of 299, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 1.53 % in 103570 diverse cancer specimens. This rate is 20.45-fold higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 2.06 % in 74463 haematopoietic and lymphoid cancers tested; 0.4 % in 1468 skin cancers tested; 0.38 % in 1712 large intestine cancers tested; 0.15 % in 743 endometrium cancers tested; 0.13 % in 856 stomach cancers tested; 0.13 % in 2889 lung cancers tested; 0.12 % in 1270 liver cancers tested; 0.11 % in 1176 ovary cancers tested; 0.05 % in 2001 central nervous system cancers tested.

Most frequent mutations with the number of reports indicated in brackets: D835Y (211); D835? (707); D835E (27).

A large number of complex mutations and insertions mutations are clustered between amino acid residues 569 and 627. Over 50 deletionsmutations occurred at amino acid residues 835 and 836. These mutation patterns are consistent with FLT3 as an oncoprotein.