Hematologic malignancies

DG Gilliland - Current opinion in hematology, 2001 - journals.lww.com
DG Gilliland
Current opinion in hematology, 2001journals.lww.com
Our understanding of the molecular pathogenesis of human hematologic malignancies has
grown at an unprecedented pace during the past decade. Many of our insights have been
gained through the cloning and characterization of chromosomal translocation breakpoints,
which have identified genes that are causally implicated in disease pathogenesis. A decade
ago only a handful of recurring chromosomal translocations had been cloned, whereas
there are now more than 100. Furthermore it has become increasingly apparent, and is …
Our understanding of the molecular pathogenesis of human hematologic malignancies has grown at an unprecedented pace during the past decade. Many of our insights have been gained through the cloning and characterization of chromosomal translocation breakpoints, which have identified genes that are causally implicated in disease pathogenesis. A decade ago only a handful of recurring chromosomal translocations had been cloned, whereas there are now more than 100. Furthermore it has become increasingly apparent, and is perhaps no surprise, that point mutations in hematopoietic transcription factors and tyrosine kinases also contribute to the pathogenesis of leukemia. Examples include the hematopoietic transcription factors RUNX1 and C/EBPα, and the hematopoietic tyrosine kinases FLT3 and c-KIT. Finally, there is now considerable evidence that acute leukemias, like other human cancers, are the consequence of more than one mutation.
The wealth and complexity of molecular genetic data presents challenging problems. There is a diversity of genotypes that exceeds our enumeration of clinical and morphologic phenotypes. Furthermore, at first glance this high degree of genetic heterogeneity might discourage molecular targeting approaches to the treatment of leukemia. For example, how does one identify therapeutic strategies that might be effective for a majority of leukemias when there are more than 100 known mutations? How do we rationally approach targeted therapy for hematologic malignancies that are the consequence of more than one mutation—is targeting one mutation adequate?
Lippincott Williams & Wilkins