Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches

摘要

Acute myeloid leukemia (AML), the most common acute leukemia in the adult, is believedto arise as a consequence of multiple molecular events that confer on primitive hematopoieticprogenitors unlimited self-renewal potential and cause defective differentiation. A number of geneticaberrations, among which a variety of gene fusions, have been implicated in the developmentof a transformed phenotype through the generation of dysfunctional molecules that disrupt keyregulatory mechanisms controlling survival, proliferation, and differentiation in normal stem andprogenitor cells. Such genetic aberrations can be recreated experimentally to a large extent, to rendernormal hematopoietic stem cells “bad”, analogous to the leukemic stem cells. Here, we wish toprovide a brief outline of the complementary experimental approaches, largely based on gene deliveryand more recently on gene editing, employed over the last two decades to gain insights into themolecular mechanisms underlying AML development and progression and on the prospects thattheir applications offer for the discovery and validation of innovative therapies.