Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by BCR-ABL1 oncogene expression. This dysregulated protein-tyrosine kinase (PTK) is known as the principal driver of the disease and is targeted by tyrosine kinase inhibitors (TKIs). Extensive documentation has elucidated how the transformation of malignant cells is characterized by multiple genetic/epigenetic changes leading to the loss of tumor-suppressor genes function or proto-oncogenes expression. The impairment of adequate levels of substrates phosphorylation, thus affecting the balance PTKs and protein phosphatases (PPs), represents a well-established cellular mechanism to escape from self-limiting signals. In this review, we focus our attention on the characterization of and interactions between PTKs and PPs, emphasizing their biological roles in disease expansion, the regulation of LSCs and TKI resistance. We decided to separate those PPs that have been validated in primary cell models or leukemia mouse models from those whose studies have been performed only in cell lines (and, thus, require validation), as there may be differences in the manner that the associated pathways are modified under these two conditions. This review summarizes the roles of diverse PPs, with hope that better knowledge of the interplay among phosphatases and kinases will eventually result in a better understanding of this disease and contribute to its eradication.

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“…The first was BCR-ABL, a protein kinase overexpressed in most CML patients and a protein responsible for uncontrolled CML cell growth and reproduction [ 26 ]). Tyrosine-protein phosphatase non-receptor type 11 (SHP2) plays an important role in CML since it is required to initiate and maintain BCR-ABL-mediated transformation, which is vital in leukemogenesis and hematopoiesis [ 27 ]). Auro-rakinase and mortalin are overexpressed in chronic myeloid leukemia, making them targets for inhibition, especially when conventional TKI inhibitors fail [ 28 , 29 ]).…”

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“…Two isoforms of AKT, a serine/threonine kinase from the AGC family of kinases, are expelled in hematopoietic stem cells. P-AKT, which has been activated, followed by PI3K activation by BCR-ABL1, can prevent apoptosis and promote cell growth [ 62 ]. By examining PTEN’s role in BCR-ABL showing Ba/F3 cells, it has been discovered that it causes the reduced activity of PTEN phosphatase and a decrease in the production of the p53 protein [ 63 ].…”

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“…This genomic aberration generates a new fusion gene, BCR-ABL1, which encodes for a tyrosine kinase held accountable for the neoplastic transformation of these cells by affecting normal cellular pathways essential for tissue homeostasis and thus causing the alteration of crucial cellular processes, such as apoptosis, cell cycle, and autophagy [ 3 , 4 ]. In this context, one primary goal of research is to identify the regulatory mechanisms antagonizing the kinase activity of BCR-ABL1 and, possibly, of other vital effectors intersecting this pathway, as players other than BCR-ABL1 have been involved in the pathogenesis of the disease [ 5 , 6 ]. The natural history of CML, prior to the advent of small molecule protein kinase antagonists, features a progression from a stable or chronic phase to an accelerated phase or to a rapidly fatal blast crisis within 3–5 years.…”