New Developments in Chronic Myeloid Leukemia: Implications for Therapy

Abstract

Context: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by overproduction of immature and matured myeloid cells in the peripheral blood, bone marrow and spleen.

Evidence acquisition: A hallmark of CML is the presence of (9; 22) (q34; q11) reciprocal translocation, which is cytogenetically visible as Philadelphia chromosome (Ph) and results in the formation of BCR-ABL1 fusion protein. This fusion protein is a constitutively active tyrosine kinase which is necessary and sufficient for malignant transformation. The introduction of imatinib, a BCR-ABL1- targeting tyrosine kinase inhibitor (TKI) has revolutionized CML therapy. Subsequently, two other TKIs with increased activity against BCR-ABL1, dasatinib and nilotinib, were developed and approved for CML patients. Nevertheless, CML therapy faces major challenges.

Results: The first is the development of resistance to BCR-ABL1 inhibitors in some patients, which can be due to BCR-ABL1 overexpression, differences in cellular drug influx and efflux, activation of alternative signaling pathways, or emergence of BCR-ABL1 kinase domain mutations during TKI treatment. The second is the limited efficiency of BCR-ABL1-TKIs in blast crisis (BC) CML. The third is the insensitivity of CML stem cells to BCR-ABL1 inhibitors. Conventional chemotherapeutics and BCR-ABL1 inhibitors which act by inhibiting cell proliferation and inducing apoptosis, are ineffective against quiescent CML stem cells.

Conclusions: A better understanding of the mechanisms that underlie TKI resistance, progression to BC, genomic instability and stem cell quiescence is essential to develop curative strategies for patients with CML.

Keywords: BCR-ABL1; Chronic Myeloid Leukemia; Imatinib; Tyrosine Kinase Inhibitors.

Figure 1.. Schematic Representation of ABL1 and BCR Genes

1a, The ABL1 gene is located on chromosome 9q34 and spans more than 230 kb. It contains two alternative first exons, exon 1b and 1a, followed by exons 2 to 11. Exon 1b is approximately 200 kb upstream of exon 1a. The breakpoints that create the Philadelphia chromosome, are scattered over a large area (more than 300 kb) at the 5’ end of the gene, either upstream of alternative exon 1b, between alternative exons 1b and 1a, or between exons 1a and 2. The BCR gene is located on chromosome 22q11 and spans approximately 135 kb. This gene contains 23 exons. In most patients with chronic myeloid leukemia, the breakpoint is in the major breakpoint cluster region that spans exons 12 - 16.

Figure 2.. BCR-ABL1 Signaling Network

Dimerization of BCR-ABL1 induces autophosphorylation and activation of the kinase, generating docking sites for adaptor proteins like GRB2. This signaling pathway results in activation of multiple downstream targets, leading to increased proliferation, enhanced survival, and perturbation of cell adhesion and migration.