Acute myeloid leukemia (AML) is caused by the blockade of hematopoietic myeloid precursors at different stages of differentiation. A subtype of AML, acute promyelocytic leukemia (APL), is a paradigm of differentiation therapy since all-trans-retinoic acid (ATRA)-based treatments are able to induce leukemic blast terminal differentiation, leading to clinical remission in the majority of APL patients. However, ATRA can lead to systemic toxicity and relapses after initial remission followed by resistance. Furthermore APL accounts for about 10-15% of AML cases and non-APL AML respond only very slightly to ATRA. Thus the search for a strategy to further sensitize AML cells to ATRA is highly needed. Retinoic acid induces differentiation of APL blasts to granulocytes, cells characterized by accumulation of secretory granules containing peptides assembled in the ER. Generally, increased protein folding demand in the ER activates a series of intracellular signal transduction pathways, the unfolded protein response (UPR). The UPR intervenes in reliving ER stress, but if such stress is too strong or prolonged it triggers pro-apoptotic pathways. We set out to investigate if the UPR plays a role in RA-dependent APL differentiation and possibly to exploit RA-induced differentiation to sensitize APL and non-APL AML cells to ER stress. We found that RA-triggered differentiation deeply altered APL cells sensitivity to ER stress. Indeed doses of tunicamycin or thapsigarging that did not adversely affect proliferating cells resulted in proliferation arrest, cell death and increased differentiation of RA stimulated APL and non-APL cell lines and, most importantly, of human primary leukemic blasts. We show that CHOP is strongly up-regulated upon induction of ER stress in RA-treated APL cells and its down-regulation by shRNA partially restored resistance. Our work suggests that modulation of the UPR in combination with RA based differentiation therapy could be an interesting strategy to target AML cells.
Retinoic Acid strongly sensitizes Acute Myeloid Leukemia cells to ER stress / Masciarelli, S.; Capuano, Ernestina.; Bellissimo, T.; Iosue, Ilaria.; Ottone, T.; Divona, M. D.; Lo-Coco, F.; Fazi, Francesco. - (2015). (Intervento presentato al convegno Gordon Research Conferences - 2015 Meeting - Stress Proteins in Growth, Development & Disease tenutosi a Lucca (Barga), Italy).
Retinoic Acid strongly sensitizes Acute Myeloid Leukemia cells to ER stress
Masciarelli S.;Capuano Ernestina.;Fazi francesco
2015
Abstract
Acute myeloid leukemia (AML) is caused by the blockade of hematopoietic myeloid precursors at different stages of differentiation. A subtype of AML, acute promyelocytic leukemia (APL), is a paradigm of differentiation therapy since all-trans-retinoic acid (ATRA)-based treatments are able to induce leukemic blast terminal differentiation, leading to clinical remission in the majority of APL patients. However, ATRA can lead to systemic toxicity and relapses after initial remission followed by resistance. Furthermore APL accounts for about 10-15% of AML cases and non-APL AML respond only very slightly to ATRA. Thus the search for a strategy to further sensitize AML cells to ATRA is highly needed. Retinoic acid induces differentiation of APL blasts to granulocytes, cells characterized by accumulation of secretory granules containing peptides assembled in the ER. Generally, increased protein folding demand in the ER activates a series of intracellular signal transduction pathways, the unfolded protein response (UPR). The UPR intervenes in reliving ER stress, but if such stress is too strong or prolonged it triggers pro-apoptotic pathways. We set out to investigate if the UPR plays a role in RA-dependent APL differentiation and possibly to exploit RA-induced differentiation to sensitize APL and non-APL AML cells to ER stress. We found that RA-triggered differentiation deeply altered APL cells sensitivity to ER stress. Indeed doses of tunicamycin or thapsigarging that did not adversely affect proliferating cells resulted in proliferation arrest, cell death and increased differentiation of RA stimulated APL and non-APL cell lines and, most importantly, of human primary leukemic blasts. We show that CHOP is strongly up-regulated upon induction of ER stress in RA-treated APL cells and its down-regulation by shRNA partially restored resistance. Our work suggests that modulation of the UPR in combination with RA based differentiation therapy could be an interesting strategy to target AML cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
