Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence
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Angela Ianniciello1,*, Pierre-Yves Dumas1,*, Claire Drullion1,*, Amélie Guitart1, Arnaud Villacreces1, Yan Peytour1, Jean Chevaleyre1,5, Philippe Brunet de la Grange1,5, Isabelle Vigon1, Vanessa Desplat1, Muriel Priault2, Persio Dello Sbarba3, Zoran Ivanovic1,5, François-Xavier Mahon4 and Jean-Max Pasquet1
1Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1035 BMGIC, Université de Bordeaux, 33076 Bordeaux Cedex, France
2UMR CNRS 5095, I.B.G.C, Université de Bordeaux, 33077 Bordeaux Cedex, France
3Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, 50134 Firenze, Italia
4INSERM U1218, Institut Bergonié, 33076 Bordeaux, France
5Etablissement Français du Sang Aquitaine-Limousin, 33075 Bordeaux, France
*These authors contributed equally to this work
Jean-Max Pasquet, email: [email protected]
Keywords: chronic myeloid leukemia, autophagy, stem cell
Received: September 01, 2016 Accepted: June 17, 2017 Published: June 30, 2017
Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O2 for 7 days) followed back by non-restricted O2 supply (normoxic culture) to mimic stem cell proliferation and commitment. Knockdown of Atg7 expression, a key player in autophagy, in K562 cell line inhibited autophagy compared to control cells. Upon 7 days at 0.1% O2 both K562 and K562 shATG7 cells stopped to proliferate and a similar amount of viable cells remained. Back to non-restricted O2 supply K562 cells proliferate whereas K562 shATG7 cells exhibited strong apoptosis. Using immunomagnetic sorted normal and CML CD34+ cells, we inhibited the autophagic process by lentiviral infection expressing shATG7 or using a Vps34 inhibitor. Both, normal and CML CD34+ cells either competent or deficient for autophagy stopped to proliferate in hypoxia. Surprisingly, while normal CD34+ cells proliferate back to non restricted O2 supply, the CML CD34+ cells deficient for autophagy failed to proliferate. All together, these results suggest that autophagy is required for CML CD34+ commitment while it is dispensable for normal CD34 cells.
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