DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia

Abstract

DNA damage and alterations in the DNA damage response (DDR) are critical sources of genetic instability that might be involved in BCR-ABL1 kinase-mediated blastic transformation of chronic myeloid leukemia (CML). Here, increased DNA damage is detected by γH2AX foci analysis in peripheral blood mononuclear cells (PBMCs) of de novo untreated chronic phase (CP)-CML patients (n = 5; 2.5 γH2AX foci per PBMC ± 0.5) and blast phase (BP)-CML patients (n = 3; 4.4 γH2AX foci per PBMC ± 0.7) as well as CP-CML patients with loss of major molecular response (MMR) (n = 5; 1.8 γH2AX foci per PBMC ± 0.4) when compared to DNA damage in PBMC of healthy donors (n = 8; 1.0 γH2AX foci per PBMC ± 0.1) and CP-CML patients in deep molecular response or MMR (n = 26; 1.0 γH2AX foci per PBMC ± 0.1). Progressive activation of erroneous non-homologous end joining (NHEJ) repair mechanisms during blastic transformation in CML is indicated by abundant co-localization of γH2AX/53BP1 foci, while a decline of the DDR is suggested by defective expression of (p-)ATM and (p-)CHK2. In summary, our data provide evidence for the accumulation of DNA damage in the course of CML and suggest ongoing DNA damage, erroneous NHEJ repair mechanisms, and alterations in the DDR as critical mediators of blastic transformation in CML.

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

“…The Chk2 kinase was activated in all samples, and the phosphorylation-specific band appeared to be strong in most patients (Figure 1b). These data are consistent with recently published evidence for ongoing DNA damage and DDR detected by activated ATM, Chk2, and γH2AX accumulation in PB-MNCs of de novo untreated CP-CML patients [39]. In contrast to strong Chk2 activation in CML cells, lysates prepared from cells obtained from PV patients in their proliferative phase showed only modest evidence of activated Chk2 (i.e., displayed lower signal of phosphorylated Chk2 compared to CML cells), whereas the unphosphorylated form of Chk2 was barely detectable in these samples (Figure 1b).…”

“…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.…”

Oxidative Stress and DNA Damage in Chronic Disease and Environmental Studies

“…To investigate whether the accumulation of ROS-induced DNA damage and defective DNA damage response (DDR) rates are associated with chronic myeloid leukemia (CML), a myeloproliferative neoplasm, the study by Popp et al [ 10 ] examined the levels of double strand breaks (DSBs) and DDR in CML patients by immunofluorescence microscopy and Western blotting. High DSB production, detected by the γH2AX foci analysis, was found in chronic, accelerated and blast phases of CML patients as well as in those with loss of major molecular response in respect to controls or CML patients with deep molecular response.…”

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

“… 56 The incidence of ACAs among CP-CML patients is 5%, while 60%-80% ACAs are detected in BP-CML. 2 , 57 , 58 Previously, the European Leukemia Network (ELN) recommended that ACAs present at the time of a new diagnosis be defined as a warning signal and that newly emerging ACAs for treatment be defined as a failure. However, it was later found that the ACA subtype could be used to predict the patient outcome.…”

“…The disease is caused by the BCR-ABL fusion gene generated from the t (9;22)(q34;q11) reciprocal translocation, encoding the BCR-ABL oncoprotein, which constitutively activates ABL kinase and drives hematopoietic cell proliferation and leukemic transformation. [1][2][3][4][5][6] CML is a natural triphasic course disease starting with the indolent CP, which is characterized by a remarkable increase in myeloid precursors and mature cells and lasts approximately 3-5 years. 7 Without therapeutic intervention, after a median interval of 3-18 months, the disease spontaneously progresses to AP and eventually to highly aggressive BP, characterized by a rapid expansion of primitive cells in the bone marrow that spill into circulation, 8,9 similar to acute leukemia.…”