Abstract
Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.
Highlights
Cells have to robustly counteract against events that can cause DNA damage, and, be ready to recognize and repair any possible error in genetic material
Activated p53 regulates the expression of a plethora of genes that are involved in multiple cellular functions, such as (i) cyclin dependent kinase inhibitor 1A (CDKN1A), by the transcription regulation of which it is able to halt the cell at the G1 phase, allowing to the cell to have sufficient time to repair the DNA damage and restore genomic stability, (ii) Bcl-2-binding component 3 (BBC3) and Bcl-2-associated X (BAX) in apoptosis or (iii) promyelocytic leukemia protein (PML) in cellular senescence [34]
As in anaplastic large cell lymphoma (ALCL), these results showed that the balance of cytoplasmic and nucleus portion of NPM-anaplastic lymphoma kinase (ALK) is crucial
Summary
Cells have to robustly counteract against events that can cause DNA damage, and, be ready to recognize and repair any possible error in genetic material. A case in point, as has been shown, is that oncogenic tyrosine kinases, such as NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) (and BCR (breakpoint cluster region)-ABL (abelson murine leukemia viral oncogene homolog 1), TEL (translocation ETS leukemia)-ABL, TEL-JAK2 (janus kinase 2)) induce DNA damage, and directly impair the normal. DNA-PKcs is a kinase protein that is involved in the non-homologous end joining (NHEJ) pathway of DNA repair. We focus on the involvement of NPM-ALK translocation in the tumor pathogenesis, by influencing pathways that are dedicated to the maintenance of genomic stability
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