Download Domanda fondamentale

Domanda fondamentale
È sufficiente attaccare esclusivamente le CSC?
Nessuno ha finora dimostrato che l'incapacità di
self-renewal delle CSC sia sufficiente ad
impedire lo sviluppo di un tumore
Acute Promyelocytic Leukemia (APL)
Myeloid differentiation
Monoblast
Promyelocytes
PML
Chr 15
RAR
Chr 17
PML RAR
t(15;17)
Leukemia-free survival (%)
Leukemogenesis is a multi-stage process
Pre-leukemia
At the pre-leukemic stage, hematopoiesis is apparently norma
Molecular mechanism of
PML-RAR action
DNMT/HMTs
RA
From DeThe and C
ATRA acts on bulk APL cells, and on LICs
APL
ATRA
Tumor Recurrenc
tumor
grows back
PML-RAR degradation
Bulk Cells
LICs
Continuous treatment with HDACi is required
for prolonging survival of leukemic mice
Continuous treatment with HDACi is required
for prolonging survival of leukemic mice
rapid growing
cells killed
tumor
grows back
An assay to measure LICs
Bulk
LIC
(Ly5.1+))
Vehicle
Treatment
No Effect
Leukemic Cells (Ly5.2)
Drug treatment
Harvest leukemic
cells (Ly5.2+)
treated/untreated
LIC Expansion
Transplant in Limiting Dilutions
(Ly5.1+)
LIC Reduction
An assay to measure LICs
Bulk
LIC
(Ly5.1+)
Vehicle
Treatment
No Effect
Leukemic Cells (Ly5.2)
Drug treatment
Harvest leukemic
cells (Ly5.2+)
treated/untreated
LIC Expansion
Transplant in Limiting Dilutions
(Ly5.1+)
LIC Reduction
ATRA treatment reduces LIC frequency ≈ 100 fold
VPA spares LICs
Limiting Dilution
Vehicle
LIC Frequency
2.5x10^4
VPA
3.9x10^4
Short-term inhibition of multiple HDACs with SAHA
tackles LICs but does not prolong survival
Survival
LIC assay
LIC Frequency
Vehicle
SAHA
2.5x10^4
2.3x10^6
In Summary…
Leukemia
ATRA
Tumor Recurrenc
?
SAHA
VPA
Bulk Cells
LICs
Eradication of APL by ATRA-SAHA-VPA
No leukemic cells
detectable