A lecture by Dr Mario Tschan (Institute of Pathology, Bern, Suisse) at CRCT, Toulouse - Lundi 17 octobre 2016 Salle Christophe Cazaux à 9h

Autophagy in retinoic acid therapy of acute myeloid leukemia

Autophagy is a lysosomal degradation process that removes and recycles cytoplasmic constituents. Autophagy is characterized by the formation of double-membraned autophagosomes, which engulf bulk cytoplasm or selected contents thereof and transfer them to lysosomes for degradation. At basal activity autophagy ensures cellular homeostasis. Moreover, autophagy is an essential cytoprotective stress response to a variety of stimuli. In tumorigenesis the effects of autophagy are clearly context-dependent. Autophagy may act as tumor suppressor by clearing cells from damaged organelles/aggregated proteins or may promote cancer progression by enabling cancer cell survival under metabolic stress. Furthermore, autophagy frequently protects cancer cells from cytotoxic therapeutic agents and also functions in cellular differentiation and development. Therefore, modulating autophagy holds great promises for novel treatment options in cytotoxic and differentiation therapies. Retinoids are naturally occurring vitamin A derivatives, which exert their functions via activation of nuclear retinoid acid receptor mediated gene expression. Due to their cyto-differentiating, pro-apoptotic and antiproliferating capacity they represent promising anti-tumor agents. The predominant form of retinoids, all-trans retinoic acid (ATRA), is successfully used to treat acute promyelocytic leukemia (APL) where it induces neutrophil differentiation of leukemic blast cells. We observed increased autophagic activity during neutrophil differentiation as well as impaired differentiation upon pharmacological inhibition of autophagy in APL cells. Next, we found significantly decreased expression of key autophagy genes in primary AML patients as compared to normal neutrophils. Moreover, knocking down key autophagy genes significantly attenuated neutrophil differentiation of APL cells. Importantly, pharmacological activation of autophagy in combination with ATRA treatment significantly boosted APL differentiation. Furthermore our data provide strong evidence for a particular, non-canonical subtype of autophagy operative during neutrophil differentiation of APL cells. Deciphering the particular autophagy pathway active during APL differentiation is a prerequisite to develop novel differentiation therapies that are based on autophagy modulation. Since our findings have been validated in non-APL cells, activation of autophagy might support neutrophil differentiation of AML cells in a more general way.

References

[1] Wampfler et al. (2015) J Leukoc Biol. 2015 Sep;98(3):357-63.

[2] Orfali et al. (2015) Exp Hematol. 2015 Sep;43(9):781-93.

[3]Haimovici et al. (2014 Leuk Res. 2014 Sep;38(9):1041-7.

[4]Brigger et al. (2014) Cell Death Dis 3:5:e1315.

Contact Dr Sylvie Giuriato, Equipe 7,sylvie.giuriato@inserm.fr