Genetic instability in inherited and sporadic leukemias.
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.
Popp
Henning D
HD
Department of Internal Medicine III, Laboratory of Leukemia Diagnostics, Ludwig-Maximilians-University-Campus Grosshadern, Marchioninistrasse 15, Munich, Germany. Henning.Popp@med.uni-muenchen.de
Bohlander
Stefan K
SK
D001752:Blast Crisis; D001816:Bloom Syndrome / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D004249:DNA Damage; D004260:DNA Repair; D004734:Energy Metabolism; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species