Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors.

Abstract

Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by the excessive proliferation of the myeloid lineage. In its initial chronic phase, the myeloid progenitor cells expand and demonstrate apparently normal differentiation. The disease may then transform into the accelerated phase, usually associated with resistance to therapy, and finally, into acute leukemic progression phase - blast crisis. Abnormal myeloid cells produce progenitors, which have lost their ability to differentiate, but retain the capacity to proliferate. The molecular hallmark of CML is the Philadelphia chromosome, resulting from reciprocal chromosome translocation, t(9;22)(q34;q11), and containing the BCR/ABL fusion gene, producing the BCR/ABL protein with a constitutive tyrosine kinase activity. BCR/ABL-positive cells have faster growth and proliferation over their normal counterparts and are resistant to apoptosis. Introduction of imatinib (IM), a tyrosine kinase inhibitor, revolutionized the therapy of CML, changing it from a fatal disease into a chronic disorder. However, some patients show a primary resistance to IM, others acquire such resistance in the course of therapy. Therefore, a small number of leukemic stem cells retains self-renewal capacity under IM treatment. Because BCR/ABL is involved in many signaling pathways, some of them may be essential for resistance to IM-induced apoptosis. The PI3K/AKT, Ras and JAK/STAT signaling pathways are involved in resistance to apoptosis and can be activated by BCR/ABL. Therefore, they can be candidates for BCR/ABL-dependent pro-survival pathway(s), allowing a fraction of CML cells to withstand treatment with tyrosine kinase inhibitors.

Dehydrocostus Lactone Suppresses Proliferation of Human Chronic Myeloid Leukemia Cells Through Bcr/Abl‐JAK/STAT Signaling Pathways

“…AND THE JAK2/STAT3/5 SIGNALING PATHWAY CML is characterized by the overexpression of the Bcr/Abl gene, which plays a crucial role in the resistance of CML cells to apoptosis [Danisz and Blasiak, 2013]. It has been reported that Bcr/Abl-JAK/STATs activity in CML was associated with the inhibition of differentiation, apoptosis, cell cycle progression, and oncogenic signaling pathways.…”

Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and -resistant chronic myeloid leukemia cells

“…Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL gene rearrangement (1,2). As a driving force for leukemogenesis of CML, the activated tyrosine kinase of BCR-ABL stimulates multiple signaling pathways that confers growth advantage and counteracts apoptosis (3)(4)(5).…”

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

“…Recently, studies have found that BCR/ABL was involved in many signaling pathways, including the PI3K/AKT, Ras and JAK/STAT signaling pathways, which are activated by BCR/ABL, resulting in malignant proliferation of CML cells. These pathways are also involved in the resistance to apoptosis in CML cells and are associated with imatinib resistance in CML patients (Danisz & Blasiak, ). Pathway enrichment involves cytokine‐cytokine receptor pathways, including tyrosine kinase receptor activity and phosphokinase receptor and androgen receptor pathway activation; TKIs are currently the primary treatment for CML patients (Arrigoni et al, ).…”