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

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 903 ◽  
Author(s):  
Jan Stetka ◽  
Jan Gursky ◽  
Julie Liñan Velasquez ◽  
Renata Mojzikova ◽  
Pavla Vyhlidalova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Polycythemia Vera ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Jak2 V617f ◽  
Damage Response

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.

scholarly journals DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia

2020 ◽  
Vol 21 (4) ◽  
pp. 1177 ◽  
Author(s):  
Popp ◽  
Kohl ◽  
Naumann ◽  
Flach ◽  
Brendel ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Blastic Transformation ◽  
Γh2ax Foci ◽  
Damage Response ◽  
Nhej Repair ◽  
Repair Mechanisms

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.

DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells

2012 ◽  
Vol 53 (10) ◽  
pp. 2004-2014 ◽  
Author(s):  
Joana Dinis ◽  
Vânia Silva ◽  
Marta Gromicho ◽  
Célia Martins ◽  
António Laires ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Imatinib Resistant ◽  
Damage Response

scholarly journals BCR/ABL and chromosomal instability: debate resolved

Blood ◽  
2012 ◽  
Vol 119 (26) ◽  
pp. 6180-6181 ◽  
Author(s):  
Martin Carroll
Keyword(s):  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Chromosomal Instability ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Nonhomologous End Joining ◽  
End Joining

In this issue of Blood, Chakraborty and colleagues provide conclusive proof that primary chronic myeloid leukemia (CML) cells from patients in chronic phase demonstrate chromosomal instability after DNA damage, suggesting that BCR/ABL, among its myriad described functions, dysregulates nonhomologous end joining (NHEJ) starting the progression of cells toward CML blast crisis.1

scholarly journals ASXL1, TP53 and IKZF3 mutations are present in the chronic phase and blast crisis of chronic myeloid leukemia

2013 ◽  
Vol 3 (11) ◽  
pp. e157-e157 ◽  
Author(s):  
J Menezes ◽  
R N Salgado ◽  
F Acquadro ◽  
G Gómez-López ◽  
M C Carralero ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase

scholarly journals An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (26) ◽  
pp. 2337-2353 ◽  
Author(s):  
Tun Kiat Ko ◽  
Asif Javed ◽  
Kian Leong Lee ◽  
Thushangi N. Pathiraja ◽  
Xingliang Liu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Integrative Model ◽  
Dna Hypermethylation ◽  
Molecular Alterations

Abstract Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

scholarly journals Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2013-2016 ◽  
Author(s):  
H Sill ◽  
JM Goldman ◽  
NC Cross
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
P16 Gene ◽  
Number Of Patients ◽  
Wide Range ◽  
Homozygous Deletions

The p16 gene, also referred to as MTS1, INK4, CDK4I, or CDKN2, at chromosome 9p21 has recently been described as a tumor suppressor that may be involved in a wide range of tumors. We have used a semiquantitative multiplex polymerase chain reaction assay to search for deletions of the p16 gene in 34 patients with chronic myeloid leukemia in blast crisis (CML BC), 19 patients with acute lymphoblastic leukemia (ALL), and 25 patients with acute myeloid leukemia (AML). Homozygous deletions of p16 exons were found in 5 of 10 (50%) patients with CML in lymphoid BC and in 5 (26%) ALL patients, but in only 1 (2%) case with AML. No deletions were found in CML BC of nonlymphoid phenotype. Comparison of chronic phase DNA or remission DNA with acute leukemia DNA in 5 individuals showed that the p16 deletions were acquired and not inherited, directly implicating these lesions in the pathogenesis of the disease. We conclude that functional elimination of the p16 gene, or a closely mapping gene, is involved in a significant number of patients with CML in lymphoid transformation.

scholarly journals Adenosine deaminase and ecto-5'-nucleotidase activities in various leukemias with special reference to blast crisis: significance of ecto- 5'-nucleotidase in lymphoid blast crisis of chronic myeloid leukemia

Blood ◽  
1981 ◽  
Vol 58 (6) ◽  
pp. 1107-1111 ◽  
Author(s):  
M Koya ◽  
T Kanoh ◽  
H Sawada ◽  
H Uchino ◽  
K Ueda
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adenosine Deaminase ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Leukemia Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Acute Myeloid Leukemia Cells

Abstract Adenosine deaminase (ADA) and ecto-5′-nucleotidase (5′-N) activities were examined in peripheral leukocytes from patients with leukemias, including nine patients with chronic myeloid leukemia (CML) in blast crisis. Four of none cases of CML in blast crisis were myeloid and the remaining lymphoid morphologically. The diagnosis of CML in lymphoid blast crisis was further contributed by the measurement of terminal deoxynucleotidyl transferase (TdT) activity. In all four cases of lymphoid blast crisis and one of myeloid blast crisis, leukemia cells had high 5′-N activity, while there was a little or no detectable activity in those from four cases of myeloid blast crisis and all of CML in chronic phase. ADA activity was high in seven of nine patients with blast crisis. Taken together, leukemia cells from two cases of lymphoid blast crisis had high ADA and 5′-N activities comparable to those in acute lymphocytic leukemia (ALL) cells. In contrast, the enzyme activities of leukemia cells from all but one patient in myeloid blast crisis were in a range similar to acute myeloid leukemia cells. The implications of these findings are as follows: (1) 5′-N may be used as a new biochemical marker of CML in lymphoid blast crisis. (2) Some lymphoid cells of CML in blast crisis have high ADA, 5′-N, and TdT activities and thus are very similar to ALL cells.

scholarly journals Molecular biology of bcr-abl1–positive chronic myeloid leukemia

Blood ◽  
2009 ◽  
Vol 113 (8) ◽  
pp. 1619-1630 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Jorge Cortes
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Oncogenic Signaling ◽  
Stem Cell Quiescence ◽  
Oncogenic Signaling Pathways

Abstract Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. Decades of research zeroing in on the role of BCR-ABL1 kinase in the pathogenesis of CML have culminated in the development of highly efficacious therapeutics that, like imatinib mesylate, target the oncogenic kinase activity of BCR-ABL1. In recent years, most research efforts in CML have been devoted to developing novel tyrosine kinase inhibitors (TKIs) as well as to elucidating the mechanisms of resistance to imatinib and other TKIs. Nonetheless, primordial aspects of the pathogenesis of CML, such as the mechanisms responsible for the transition from chronic phase to blast crisis, the causes of genomic instability and faulty DNA repair, the phenomenon of stem cell quiescence, the role of tumor suppressors in TKI resistance and CML progression, or the cross-talk between BCR-ABL1 and other oncogenic signaling pathways, still remain poorly understood. Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML.

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