Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

Abstract

Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions.CML is characterized by an indolent, chronic phase (CP) preceding an acute transformation to BC. Failure of DNA damage repair and loss or malfunction of DDR components accompanied by accumulation of DNA damage and genomic instability has been considered in CML evolution [38,39]. It was proposed that BCR-ABL-expressing cells feature reduced activation of the ATR-Chk1-mediated DDR signaling, with ensuing accumulation of substantial genomic instability due to replication stress and oxidative damage. Mechanistically, such disruption of ATR-dependent signaling was attributed to nuclear import of BCR-ABL after DNA damage and its binding to ATR [40]. However, contrasting data were also reported, showing that BCR-ABL does activate ATR-Chk1 signaling, reflecting responsiveness of BCR-ABL-positive myeloid cells to DNA damage following genotoxic treatment [41]. Some studies also addressed functionality of the ATM-Chk2 signaling axis in CML. Thus, c-Abl is a nuclear tyrosine kinase activated by DNA damage in an ATM-dependent manner [42,43]. Even though the BCR-ABL is predominantly localized to the cytoplasm [44], the aforementioned ability of BCR-ABL translocation to the nucleus after DNA damage led to a proposal that BCR-ABL and c-Abl share multiple protein interactions including that with ATM [40]. As a consequence, ATM-mediated activatory phosphorylation of Chk2 was detected in BCR-ABL-expressing cellular models and...

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

“…The DNA damage response (DDR) deregulation that leads to DNA damage and genomic instability has been implicated in the CML evolution, leading to TKI resistance and disease transition from CP-CML to more malignant stages [ 48 , 49 , 50 ]. This fact is supported by the higher frequency of copy number alterations and numerical and structural chromosomal changes observed in CML patients in BC compared with those in CP—a sign of increasing genomic instability [ 49 ].…”

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis

“…MDM2 inhibition has also been shown to enhance apoptosis of polycythemia vera (PV) progenitor cells [ 155 ]. Furthermore, the balance of stress responses in MPN progenitors is believed to be tightly regulated to survive the stress of an inflammatory microenvironment, enhancing the survival of disease-driving cells [ 156 ]. In addition, the loss of p53 function promotes post-MPN leukemic transformation [ 77 , 157 ].…”

Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

“…An early occurrence of JAK2V617F before the appearance of TET2/DNMT3A provides time for uniparental disomy to develop; alternatively, the more aggressive PV phenotype may be caused by an earlier stage HSC/progenitor that acquired the genetic lesion. The JAK2V617F mutation has been considered to induce genomic instability [89], and although it has been argued that these results were obtained from model systems that might not reflect human MPNs [90], it is intriguing to consider if the increased genetic instability could be a consequence of cellular hyper-proliferation/turnover accelerating the 'molecular clock'-a premature aging, increasing the risk of acquiring additional mutations and subsequent malignant transformation.…”