Title:Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem, Progenitor and Stromal Cell Interplay
Volume: 18
Issue: 4
Author(s): Danilo Perrotti, Giovannino Silvestri, Lorenzo Stramucci, Justine Yu and Rossana Trotta
Affiliation:
Keywords:
Stem cells, microenvironment, chronic myeloid leukemia, hematopoietic stem cell.
Abstract: The use of imatinib, second and third generation ABL tyrosine kinase inhibitors (TKI) (i.e.
dasatinib, nilotinib, bosutinib and ponatinib) made CML a clinically manageable and, in a small percentage
of cases, a cured disease. TKI therapy also turned CML blastic transformation into a rare event;
however, disease progression still occurs in those patients who are refractory, not compliant with TKI
therapy or develop resistance to multiple TKIs. In the past few years, it became clear that the BCRABL1
oncogene does not operate alone to drive disease emergence, maintenance and progression. Indeed,
it seems that bone marrow (BM) microenvironment-generated signals and cell autonomous BCRABL1
kinase-independent genetic and epigenetic alterations all contribute to: i. persistence of a quiescent
leukemic stem cell (LSC) reservoir, ii. innate or acquired resistance to TKIs, and iii. progression
into the fatal blast crisis stage. Herein, we review the intricate leukemic network in which aberrant, but
finely tuned, survival, mitogenic and self-renewal signals are generated by leukemic progenitors, stromal
cells, immune cells and metabolic microenvironmental conditions (e.g. hypoxia) to promote LSC
maintenance and blastic transformation.
