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Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem,
Progenitor and Stromal Cell Interplay
#MMPMID27307150
Perrotti D
; Silvestri G
; Stramucci L
; Yu J
; Trotta R
Curr Drug Targets
2017[]; 18
(4
): 377-388
PMID27307150
show ga
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.
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