Cellular origin of prognostic chromosomal aberrations in AML patients

Acute myeloid leukemia (AML) represents an aggressive cancer entity, whose malignant cells respond abnormally to regulatory stimuli and have lost the ability to differentiate and become fully mature blood cells.1, 2 AML evolves through accumulation of independent genetic aberrations, including chromosomal structural rearrangements and single nucleotide variants (SNVs).

Conventional AML diagnostics and recent seminal next-generation sequencing (NGS) studies have identified more than 200 recurrent genetic aberrations presenting in various combinations in individual patients. Significantly, many of these aberrations occur in normal hematopoietic stem and progenitor cells (HSCs/HPCs) before definitive leukemic transformation through additional acquisition of a few (that is, mostly 1 or 2) leukemia-promoting driver aberrations.

NGS studies on sorted bone marrow (BM) populations of AML patients with a normal karyotype have demonstrated the presence of prognostic driver aberrations (that is, NPM1, FLT3-ITD and FLT3-TKD) in committed HPCs but not in multipotent HSCs. However, the HSC populations lacking the prognostic driver aberrations contained preleukemic clones harboring a series of recurrent molecular aberrations that were present in the fully transformed committed HPCs together with the prognostic driver aberration.

Adding to this vast heterogeneity and complexity of AML genomes and their clonal evolution, a recent study of a murine AML model demonstrated that t(9;11) AML originating from HSCs responded poorly to in vivo chemotherapy treatment as compared with t(9;11) AML originating from HPCs.