DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance

TY - JOUR

T1 - DNA damage accumulation and repair defects in acute myeloid leukemia

T2 - implications for pathogenesis, disease progression, and chemotherapy resistance

AU - Esposito, Maria Teresa

AU - So, Chi Wai Eric

PY - 2014/12

Y1 - 2014/12

N2 - DNA damage repair mechanisms are vital to maintain genomic integrity. Mutations in genes involved in the DNA damage response (DDR) can increase the risk of developing cancer. In recent years, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia (AML) or of disease relapse. Moreover, a growing body of literature has indicated that epigenetic silencing of DDR genes could contribute to the leukemogenic process. In addition, a variety of AML oncogenes have been shown to induce replication and oxidative stress leading to accumulation of DNA damage, which affects the balance between proliferation and differentiation. Conversely, upregulation of DDR genes can provide AML cells with escape mechanisms to the DDR anticancer barrier and induce chemotherapy resistance. The current review summarizes the DDR pathways in the context of AML and describes how aberrant DNA damage response can affect AML pathogenesis, disease progression, and resistance to standard chemotherapy, and how defects in DDR pathways may provide a new avenue for personalized therapeutic strategies in AML.

AB - DNA damage repair mechanisms are vital to maintain genomic integrity. Mutations in genes involved in the DNA damage response (DDR) can increase the risk of developing cancer. In recent years, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia (AML) or of disease relapse. Moreover, a growing body of literature has indicated that epigenetic silencing of DDR genes could contribute to the leukemogenic process. In addition, a variety of AML oncogenes have been shown to induce replication and oxidative stress leading to accumulation of DNA damage, which affects the balance between proliferation and differentiation. Conversely, upregulation of DDR genes can provide AML cells with escape mechanisms to the DDR anticancer barrier and induce chemotherapy resistance. The current review summarizes the DDR pathways in the context of AML and describes how aberrant DNA damage response can affect AML pathogenesis, disease progression, and resistance to standard chemotherapy, and how defects in DDR pathways may provide a new avenue for personalized therapeutic strategies in AML.

KW - ACUTE PROMYELOCYTIC LEUKEMIA

KW - DOUBLE-STRAND BREAKS

KW - ACUTE MYELOBLASTIC-LEUKEMIA

KW - COMPLEX ABERRANT KARYOTYPE

KW - HEMATOPOIETIC STEM-CELLS

KW - HOMOLOGY-DIRECTED REPAIR

KW - T(8/21) FUSION PROTEIN

KW - BASE-EXCISION-REPAIR

KW - TOPOISOMERASE-II

KW - MICROSATELLITE INSTABILITY

U2 - 10.1007/s00412-014-0482-9

DO - 10.1007/s00412-014-0482-9

M3 - Literature review

SN - 0009-5915

VL - 123

SP - 545

EP - 561

JO - Chromosoma

JF - Chromosoma

IS - 6

ER -