SC

SC

SC

SC

SC

PSC

PSC

PSC

p21

p53 asymmetric division

In HSC cell

Transient DNA

damage

(Numb1, Prospero, BRAT, etc.)

Transient DNA damage in HSC induces DNA repair and activate p21 active - p53 independent self renewal by

asymetric division

In PSC cell

PSC

PSC

PSC

PSC

PSC

PSC

PSC

PSC

p21

p53 symmetric division

Transient DNA

damage

Transient DNA damage in PSC induces DNA repair and activate p53 dependent self renewal by symetric division

In LSC cell

LSC

LSC

p21

p53

symmetric division

Oncogene expressionAML-ETO

PML-RARa

LSC

LSC

LSC

LSC

LSC

LSC

Oncogene expression in LSC ( surrogate of DNA damage) induces DNA repair and activate p21 active - p53

independent self renewal by symmetric division

In LSC cell

LSC

LSC

p21

p53

symmetric division

Oncogene expressionAML-ETO

PML-RARa

LSC

LSC

LSC

LSC

LSC

LSC

MYC

symmetric division

asymmetric division

P21 high and p53 down–regulation activate Myc dependent

switch to asymmetric division to symmetric division

O2 = 40%

Conventional Chemotherapy

or TKI

Conventional Chemotherapy

or TKI

(ex. CD33+)

0,1%

symmetric division

LSC

LSC

LSC

LSC

LSC

LSC

SC

SC

SC

SC

SC

SC

SC

SC

p21

p53

Transient DNA

damage

symmetric division

DNA repair in SCs is never complete, leading to the progressive accumulation of persistent DNA damage and

loss of self renewal

γH2AX

Stem cells have evolved a p21-dependent response to DNA damage that leads to their immediate expansion….

senescence

…and limits their long-term survival

LSC

LSC

LSC

LSC

LSC

LSC

LSC

LSC

p21

p53

oncogene

symmetric divisionγH2AX

Leukemia Stem cells have evolved a p21-dependent p53 independent response, to DNA damage induced by

oncogene expression, that leads to their immediate expansion, due to symmetric division but …. extend their

long-term survival

The P21 checkpoints is activated in leukemiaOncogene expression into HSCs induces DNA-damage

constitutive activation of P21 and extended self renewal

suppression of apoptosis cell cycle entrysymmetric divisionsdna repair extended self renewal

LSC

LSC

LSC

LSC

LSC

LSC

LSC

LSC

p21

p53

oncogene

symmetric divisionγH2AX

The mdm2-mdm4 inhibition restore p53 activation, MYC silencing and p21 down regulation in leukemia

induction of apoptosis cell cycle stopasymmetric divisionsdna repair stop reduced self renewal

RO34567

MDM2

p21 -/-

The p21 down regulation resembles the mouse model P21-/-

LSC

LSC

LSC

LSC

LSC

LSC

LSC

LSC

p21

p53

oncogene

symmetric divisionγH2AX

The mdm2-mdm4 inhibition restore p53 activation, MYC silencing and p21 down regulation in leukemia

induction of apoptosis cell cycle stopasymmetric divisionsdna repair stop reduced self renewal

RO34567

MDM2

The Chk1 inhibition also restore p53 activation and increase sensibility to chemotherapy

CHK1 inhibitor

LSC

LSC

LSC

LSC

LSC

LSC

LSC

LSC

p21 p53

ONCOGENEAML-ETO PML-RARa

symmetric division

Killer T Cell

CD4 T cell (primed with p21-/- leukemia stem cell) induced a “kill me signaling” on damaged LSC

Pelicci PG personal comunication

LSC

LSC

LSC

LSC

LSC

LSC

LSC

LSC

p21 p53

ONCOGENEAML-ETO PML-RARa

symmetric division

Killer T Cell

CD4

T Cell

May p53 reactivation and p21 inhibition restore co-stimulatory signaling and cooperate to immunological

exaustion of damaged LCS?

Which is the costimulatory receptor involved?

Institute of Hematology “L. and A. Seràgnoli”, Bologna Cristina Papayannidis, Stefania Paolini, Maria Chiara Abbenante, Emanuela Ottaviani, Viviana Guadagnuolo, Sarah Parisi, Ilaria Iacobucci, Giorgia Simonetti, Anna Ferrari, ……

Gabriele Galli……………………………………..…………………………………….

Chiara Sartor,

Acknowledgments

Supported by: FP7, European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna