ABL1

ABL1 gene is a proto-oncogene that encodes a protein tyrosine kinase, which is involved in a variety of cellular processes, including cell division, adhesion, differentiation and stress response. Mutation of ABL1 may cause carcinogenesis in normal cells. Chromosomal translocation T (9; 22)(q34; Q11) formed an ultra-short chromosome 22 and an ultra-long chromosome 9. The ultra-short chromosome 22 was called the Philadelphia chromosome, which created a new gene that fused the extreme 5' portion of ABL1 into the 3' portion of the BCR gene, called BCR-ABL. The BCR-ABL fusion exhibits cytoplasmic localization, activates the JAK/STAT, PI3K/AKT, and RAS pathways, and induces tyrosine phosphorylation of Crk1 , Shc, Syp, Fes, Vav, and paxillin proteins, promoting cell signaling or cell growth (PMID: 11289094). Expression of the BCR-ABL gene tells abnormal blood cells to produce excessive amounts of a protein called tyrosine kinase, a constitutionally activated oncotyrosine kinase that causes ligand independent activation of signaling pathways in hematopoietic cells. Tyrosine kinases promote cancer by causing uncontrolled growth of certain blood cells.

Tyrosine kinase inhibitors (TKIs) strongly interfere with the interaction between BCR-ABL1 oncoprotein and adenosine triphosphate (ATP), thereby preventing malignant cell proliferation. Imatinib inhibits phosphorylation of proteins involved in cell signal transduction by competitively inhibiting ATP-binding sites of BCR-ABL1 oncoprotein. It also blocks platelet-derived growth factor receptors (PDGFR) and C-Kit tyrosine kinases (PMID: 10619854), patients who are resistant or intolerant to imatinib require other treatment options. Dasatinib is a second-generation oral TKI with a titer 350 times higher than imatinib in vitro. Dasatinib inhibits BCR-ABL and Src family kinases and inactivates important cellular signaling pathways. Dasatinib is a multi-target kinase inhibitor that can be used in patients with imatinib resistance or intolerance (PMID: 17496201). Nilotinib is a structural analog of imatinib, in vitro, the affinity for ATP-binding sites on BCR-ABL1 is 30-50 times greater (PMID: 15710326). Like dasatinib, nilotinib initially showed the ability to induce hematological and cytogenetic responses in patients who had failed the treatment of imatinib. Bosutinib is a potent SRC/ABL dual kinase inhibitor. The drug was first approved for adults with CML resistance and/or tolerance to prior treatment (PMID: 18056843), which is called first-line therapy. Asciminib is an allosteric inhibitor that binds to the myristyl site of the BCR-ABL1 protein and locks BCR-ABL1 into its inactive conformation by a mechanism different from all other ABL kinase inhibitors. Asciminib targets both natural and mutated BCR-ABL1 fusion genes as well as the T315I mutation. It has activity on most single mutants, but has no obvious effect on compound mutants (PMID: 31826340, PMID: 31543464). Ponatinib is a third-generation kinase inhibitor targeting the T315I mutation. In different trials, ponatinib has shown activity against the natural BCR-ABL1 kinase and some ABL1 mutations. Ponatinib is currently designated for each stage of treatment in patients with chronic myelogenous leukemia (CML) with dasatinib and nilotinib resistance or intolerance, as well as in patients with T315I mutations. Ponatinib is also indicated for Ph + Acute lymphoblastic leukemia (ALL) (PMID:28969556).