Abstract
The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies.
Highlights
BCR-ABL1 is a multidomain, constitutively active, chimeric tyrosine kinase that results from a reciprocal translocation between chromosomes 9 and 22—t(9;22)(q34;q11)—characteristic of Philadelphia chromosome(Ph1)-positive leukemia [1]
Depending on the breakpoint on chromosome 22 at the BCR gene, three major isoforms of BCR-ABL1 can be produced: the 185kDa, 210kDa, and 230kDa proteins found in acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and chronic neutrophilic leukemia (CNL), respectively [2,3,4]
The discovery that constitutive BCR-ABL1 tyrosine kinase activity was crucial for the development of CML [96] warranted a TK-targeting therapeutic strategy
Summary
BCR-ABL1 is a multidomain, constitutively active, chimeric tyrosine kinase that results from a reciprocal translocation between chromosomes 9 and 22—t(9;22)(q34;q11)—. Depending on the breakpoint on chromosome 22 at the BCR (break point cluster) gene, three major isoforms of BCR-ABL1 can be produced: the 185kDa, 210kDa, and 230kDa proteins found in acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and chronic neutrophilic leukemia (CNL), respectively [2,3,4]. 2022, 14, 215 domains, in addition to a nuclear translocation signal (NTS) sequence, sites for phosphor-2 of 22 ylation by protein kinase C (PKC), and a proline-rich sequence (Figure 1) Among all these domains, the SH1 region is the most conserved during evolution and contains the catalytic family/guanine nucleotide exchange factors (Rho/GEF) kinase domain, and SH2 dosite essential for themains initiation of signaling pathways that result in cellular transformation, capable of binding adaptor molecules, such as growth factor receptor-bound protein including dysregulated proliferation and resistance to apoptosis
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