Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence

• Published in: Oncotarget Vol. 8; no. 57; pp. 96984 - 96992
• Main Authors: Ianniciello, Angela, Dumas, Pierre-Yves, Drullion, Claire, Guitart, Amélie, Villacreces, Arnaud, Peytour, Yan, Chevaleyre, Jean, Brunet de la Grange, Philippe, Vigon, Isabelle, Desplat, Vanessa, Priault, Muriel, Sbarba, Persio Dello, Ivanovic, Zoran, Mahon, François-Xavier, Pasquet, Jean-Max
• Format: Journal Article
• Language: English
• Published: United States Impact journals 14.11.2017; Impact Journals LLC
• Subjects: Biochemistry; Biochemistry, Molecular Biology; Cancer; Cell Behavior; Cellular Biology; Hematology; Human health and pathology; Life Sciences; Research Paper; stem cell; chronic myeloid leukemia; autophagy
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.18904

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% O for 7 days) followed back by non-restricted O supply (normoxic culture) to mimic stem cell proliferation and commitment. Knockdown of expression, a key player in autophagy, in K562 cell line inhibited autophagy compared to control cells. Upon 7 days at 0.1% O both K562 and K562 shATG7 cells stopped to proliferate and a similar amount of viable cells remained. Back to non-restricted O 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 O 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.