Cancer

Chronic myeloid leukemia (CML); Precursor B-cell acute lymphoblastic leukemia; Precursor T-cell acute lymphoblastic leukemia;

ABL1 is a known oncoprotein (OP), although the wild-type form of ABL1 may be a tumour-suppressor protein. 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. Translocation t(9;22)(q34;q11)result in chimeric proteins from BCR and ABL1, and this is a cause of chronic myeloid leukemia (CML). The translocation also produces a BCR-ABL found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). BCR-ABL fusion protein results in constitutively active phosphotransferase activity by inhibiting 3BP1/ABL interaction. BCR-ABL induces the Ras, PI3K, and Myc cell proliferation pathways. The most common mutations are clustered within the kinase catalytic domain. T315 is near kinase Subdomain III. G250 and E255 are located around the ATP-binding kinase Subdomain I. It is likely that these common mutations may inactive Abl1's catalytic activity. BCR-Abl1 is found in the cytoplasm and nucleus. The phosphorylation of cytoplasmic proteins and receptors in the plasma membrane may result in a gain of function of Abl1 to stimulate cell proliferation.
 

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= -64, p<0.014); Large B-cell lymphomas (%CFC= +84, p<0.009); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +76, p<0.059); Ovary adenocarcinomas (%CFC= +55, p<0.059); Prostate cancer - primary (%CFC= +192, p<0.0001); Skin fibrosarcomas (%CFC= +83); Skin melanomas - malignant (%CFC= +171, p<0.0001); T-cell prolymphocytic leukemia (%CFC= +54, p<0.035); and Uterine leiomyomas (%CFC= -59, p<0.056). The COSMIC website notes an up-regulated expression score for ABL1 in diverse human cancers of 322, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 192 for this protein kinase in human cancers was 3.2-fold of 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: 0.4 % in 34454 diverse cancer specimens. This rate is 5.3-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: 1.49 % in 7546 haematopoietic and lymphoid cancers tested; 0.4 % in 1490 large intestine cancers tested; 0.26 % in 1100 skin cancers tested; 0.19 % in 708 endometrium cancers tested; 0.13 % in 856 stomach cancers tested; 0.09 % in 1106 ovary cancers tested; 0.08 % in 2357 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: T315I (302); G250E (133); E255K (116); E255V (29); Y253H (103); Y253F (16); M351T (100); M244V (90); F317L (82); F359V (71); H396R (41); E355G (36); Q252H (30); E459K (24).

Most point mutations are located within the protein kinase catalytic domain.