Genetic instability in inherited and sporadic leukemias

Abstract

Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies.

Tumor hypoxia as a driving force in genetic instability

“…Unrepaired DSBs can lead to formation of deletions, insertions, translocations and amplifications [83,84]. For example, cells deficient for BRCA1/2 develop spontaneous gross chromosomal aberrations [85-89].…”

Alterations in the Reactive Oxygen Species in Peripheral Blood of Chronic Myeloid Leukaemia Patients from Northern India

“…Further oxidative stress potentially induces genetic alterations that would aid in maintenance of leukaemic phenotype by creating genetic heterogeneity which is essential for progression of any cancer. The DNA damaging effect of ROS could play a central role in placing sporadic leukaemia as the most frequent type amongst all the categories of leukaemia [40]. In addition, ROS also induces mutations in kinase domain of the BCR-ABL fusion protein which leads to drug resistance [41].…”

Applying molecular epidemiology in pediatric leukemia

“…Bloom syndrome is an AR disease due to BLM germline mutations, which is a helicase gene integral for double stranded DNA break repair 84. Bloom syndrome lymphocytes reveal a high frequency of characteristic sister chromatid exchanges and quadriradial configurations 85 86.…”