acute promyelocytic leukemia ( apl ) is a subtype of aml that can be distinguished from other subtypes by distinct cytogenetic and clinical features . more specifically , more than 95% of patients with apl bear the t(15;17 ) translocation that encodes the pml / rar fusion protein . this fusion oncoprotein suppresses granulocyte development at the promyelocytic stage of differentiation and causes malignant transformation of hematopoietic progenitor cells by acting as a transcriptional repressor of gene expression . all - trans retinoid acid induced disease remission in apl patients by interacting with its ligand , causing proteolytic degradation of the oncoprotein and consequent granulocyte differentiation of apl cells , . in addition , low - dose arsenic trioxide has been reported to be remarkably effective in treating apl by inducing differentiation , whereas high dose has been reported to trigger apoptosis by causing proteolytic degradation of pml / rara. the molecular mechanism by which arsenic trioxide degrades pml / rara involves pml sumoylation and subsequent polyubiquitination and proteolytic degradation of both pml and pml / rara by a protein molecule called rnf4. all - trans retinoic acid and arsenic trioxide can act synergistically to cause leukemia regression through distinct mechanisms that lead to pml / rara degradation , ultimately resulting in clinical remission of apl , . the ubiquitin - proteasome system is largely responsible for degradation of short - lived soluble proteins and misfolded proteins following their labeling with polyubiquitin chains . previous studies have implicated that the ubiquitin - proteasome system plays an important role in therapy - induced degradation of pml / rara . sumo - conjugated pml , rnf4 and components of this system , are corecruited to nuclear compartments called pml nuclear bodies in the presence of arsenic trioxide . both pml and rara are targeted primarily to the nucleus , and the pml / rara chimera is detected mainly within the nucleus of interphase cells . thus , therapy - induced degradation of pml / rara is largely thought to occur within the nuclear compartment because pml / rara , together with ubiquitin and components of the ubiquitin - proteasome system , are recruited to pml nuclear bodies during the first few hours of arsenic trioxide treatment . the pml / rara oncoprotein is prone to aggregation , which makes it a good substrate for autophagic degradation . its ability to form protein aggregates is possibly attributable to the pml moiety of the fusion protein , which contains a tripartite motif domain . together with sumo - conjugated residues and a sumo - interacting domain , this tripartite motif in pml facilitates the formation of protein - protein interaction networks , . further , the pml / rara chimera may adapt a different conformation that renders it more prone to aggregation than pml or rara expressed from non - rearranged genes . because of its highly insoluble conformation , the pml / rara oncoprotein may be subjected to clearance by the same or similar mechanisms that degrade other types of misfolded or aggregation - prone proteins in the cell . consistent with this , cytoplasmic pml / rara - containing particles formed by ectopic expression of pml / rara and cytoplasmic pml - positive structures in nb4 cells were found to colocalize with ubiquitin , p62 , and lc3 , which are involved in autophagy - dependent degradation of protein aggregates . p62 contains a ubiquitin - binding domain and an lc3-interacting region and is therefore able to link ubiquitinated cargo to the core autophagic machinery , . because autophagy is a cytoplasmic degradation mechanism , proteolytic clearance of this oncoprotein also occurs in the cytoplasm , in addition to its aforementioned degradation via the nuclear compartment . it supports the notion that ubiquitin is a signal for autophagic degradation of pml / rara . interestingly , a cytoplasmic compartment referred to as cytoplasmic assemblies of pml and nucleoporins , which appears after mitotic cell division and contains pml or pml / rara , was cleared from nb4 cells in the presence of all - trans retinoic acid , suggesting a possible link between the stability of these cytoplasmic structures and autophagic activity . arsenic trioxide is a potent inducer of autophagy in acute leukemia cells , and such induction is dependent on activation of the mek / erk pathway but uncoupled from jnk . experiments using chloroquine , a pharmacologic autophagy inhibitor , revealed that the inhibitory effects of arsenic trioxide on primary leukemic progenitors are mediated in part via induction of autophagic cell death . the critical role of autophagy in the anti - leukemic effects of arsenic trioxide was further established by experiments in which key elements of the autophagic pathway , such as beclin1 and atg7 , were knocked down by using rna interference . previous evidence shows that in addition to apoptosis , arsenic trioxide induces autophagy in the human tlymphocytic leukemia cell line molt-4 . indeed , the catabolism of the pml / rara oncoprotein is largely affected by autophagy , and its degradation in cells treated with arsenic trioxide or all - trans retinoic acid depends upon and relates with increased autophagic activity . autophagy also has a stimulatory role on the differentiation of nb4 apl cells , suggesting that this degradation pathway potentiates therapy - induced differentiation of apl cells . this observation supports our previous finding that autophagy is essential for vitamin d3-induced differentiation of leukemia cells . autophagy also plays a critical role in the anti - leukemic effects of arsenic trioxide in primary hematopoietic progenitors from aml patients . emerging evidence suggests that treating malignant cells with arsenic trioxide results in negative feedback activation of cellular pathways that counteract apoptosis , implicating autophagy as a mechanism for the suppressive effects of arsenic trioxide on primitive leukemic progenitors . the findings of this study raise the potential that agents promoting autophagy can sensitize leukemia cells to the suppressive effects of arsenic trioxide . autophagic death of acute lymphoblastic lymphoma cells treated with dexamethasone was recently shown to be dependent on the pml protein , which is known to inhibit mammalian target of rapamycin ( mtor ) activity . thus , mtor - regulated autophagy may play a general role in the development and treatment of leukemia . previous studies show that the ubiquitin - proteasome system facilitates clearance of pml / rara induced by all - trans retinoic acid and arsenic trioxide . autophagy and proteasome - dependent degradation may thus cooperate in therapy - induced clearance of the apl - associated oncoprotein . in line with this finding , proteolytic crosstalk has been reported to clearly exist between the autophagy and ubiquitin - proteasome systems . furthermore , proteolytic degradation of pml / rara by caspases and lysosomal proteases has also been reported , suggesting the existence of multiple proteolytic pathways with a potential to target pml / rara for degradation . however , because autophagy appears to become markedly induced in the presence of all - trans retinoic acid and arsenic trioxide , this degradation pathway may have a determinant role in therapy - induced pml / rara clearance . thus , both all - trans retinoic acid and arsenic trioxide induce clinical remission in apl patients by stimulating mtor - dependent autophagy and causing concomitant autophagic degradation of the apl - associated oncoprotein pml / rara . consistent with the above observations , a recent report indicated that autophagy regulates leukemic myeloid cell differentiation via p62/sqstm1-mediated degradation of pml / rara oncoprotein . pml / rara has been shown to enhance constitutive autophagic activity through inhibition of the akt / mtor signaling pathway . another apl - specific fusion protein , the t(11;17)-associated plzf / rara , causes a different subtype of human apl . patients with apl positive for t(11;17 ) do not respond to treatment with either all - trans retinoic acid or arsenic trioxide. however , whether activation of autophagy is essential to degrade the plzf / rara fusion protein is unknown . apl patients who undergo all - trans retinoic acid monotherapy may eventually suffer relapse , as all - trans retinoic acid is apparently unable to eradicate the leukemic population . in normal hematopoiesis , all - trans retinoic acid not only induces differentiation of committed myeloid cells but may also enhance the self - renewal capabilities of stem cells and progenitors , . therefore , all - trans retinoic acid has dual effects on the apl leukemic cell population : induction of differentiation in the mature blast population , resulting in a complete remission , and conversely , induction of proliferation and/or self - renewal of leukemic stem cells . these dual effects probably explain the failure to achieve complete molecular remission and the tendency for relapse after all - trans retinoic acid monotherapy . in contrast , arsenic trioxide can induce complete molecular remission and does not seem to exert any toxic effects on hematopoietic stem cells . paradoxically , all - trans retinoic acid - induced up - regulation of beclin1 has been reported to prolong the life span of differentiated acute promyelocytic leukemia cells , whereas down - regulation of autophagy by sirna - mediated knockdown of s100a8 enhanced arsenic trioxide - induced leukemia cell death . in aml cell lines lacking known oncoprotein expression , activation of autophagy can also cause leukemia cell demise . 1,25-dihydroxyvitamin d3 , the hormonally active form of vitamin d3 , was also tried in leukemia therapy . these effects are dependent on akt down - regulation , vitamin d3 disassociation with raf1 , and subsequent activation of raf / mek / erk2 mapk signaling . in turn , cyclin - dependent kinase inhibitors are up - regulated , and retinoblastoma protein undergoes dephosphorylation and binding to transcription factors e2f1 and c / ebpa. the vitamin d3 analog eb1089 was initially reported to be able to induce apoptosis via a p53-independent mechanism involving p38 mapk activation and erk mapk inactivation in b - cell chronic lymphocytic leukemia cells . more recent studies showed that eb1089 triggered autophagy in breast cancer cells , again suggesting that the anticancer effects of the same compound may vary depending on cell types . although vitamin d3 shows promise in counteracting tumors , significant supraphysiologic concentration of this compound is required for antineoplastic effects . such concentrations are not achievable in patients due to predictable hypercalcemia and hypercalcuria resulting from the increased intestinal absorption of calcium and the calcium - mobilizing properties of vitamin d3 . to reduce the risk of vitamin d3-induced hypercalcemia and the possible immunosuppressive effects of its analogs , a combination of low - dose vitamin d3 or its analogs with another non - immunosuppressive agent that enhances differentiation but not the levels of circulating calcium has been pursued . for example , combinations of vitamin d3 with docetaxel , dexamethasone , paclitaxel , carboplatin , and carnosic acid were tried in several types of cancers and cancer model cell lines. however , the current combinatorial therapies with vitamin d3 in the preclinical stage are restricted to differentiation effects , thus limiting the efficacy on cancer cell suppression . a better understanding of the mechanisms by which vitamin d3 exerts suppressive effects on tumor cells is needed to develop vitamin d3 analogs and combinatorial therapies with better antineoplastic effects . we showed that vitamin d3 triggers autophagic death by up - regulating beclin1 and triggering differentiation but inhibiting apoptosis in myeloid leukemia cells . knockdown of beclin1 not only crippled vitamin d3-induced autophagy but also inhibited vitamin d3-induced differentiation and activated apoptotic signaling . we further demonstrated that additional up - regulation of autophagy dramatically improved the antineoplastic effect of vitamin d3 on human myeloid leukemia cells , suggesting a better strategy for combating leukemia . a number of chemical compounds including arsenic trioxide , , , , , vitamin d3 , vitamin k2 , eupalinin a ( sesquiterpene lactone ) , bay11 - 7082 ( nf-b inhibitor ) , morphinone ( a morphin derivative ) , apo866 ( nad biosynthesis inhibitor ) , and platonin have been reported to be able to induce leukemia cell death via activation of autophagy ( table 1 ) . studies on autophagy in leukemia have been limited to in vitro leukemia cell models derived from leukemia patients , and there are still few publications on autophagy in early leukemogenesis . autophagy is a highly context - dependent process that serves different functions in leukemia and solid cancers . in solid tumors , maintaining nutrient supply is difficult , and autophagy serves as an adaptive survival mechanism for the adverse nutrient supply circumstances . however , in leukemia cells in the blood that do not face a nutrient supply challenge , enhanced activation of autophagy degrades oncogenic fusion proteins to promote terminal differentiation or  over - eats despite its observed role in the development and maintenance of cancer in animal models and its opposing effects in response to a wide array of cancer therapies , autophagy in human aml cells predominantly drives a cytodestructive cascade that induces clearance of oncogenic fusion proteins and leads to cell death . thus , autophagy may be a new strategy for targeted perturbation of oncogenic proteins in certain type of acute myeloid leukemia . a recent study also showed that autophagy is essential to maintain normal hematopoietic stem cell function in quiescence , self - renewal , and multilineage differentiation . the autophagy pathway in stem cells may thus restrain transformation and prevent cancer by removing free radicals and limiting damage within stem cells , thereby protecting normal stem cells from germination of leukemia . future strategies for tackling leukemogenesis may focus more on the early prevention of transformation at hematopoietic stem cell level .
despite its dual role in determining cell fate in a wide array of solid cancer cell lines , autophagy has been robustly shown to suppress or kill acute myeloid leukemia cells via degradation of the oncogenic fusion protein that drives leukemogenesis . 
 however , autophagy also induces the demise of acute leukemia cells that do not express the known fusion protein , though the molecular mechanism remains elusive . nevertheless , 
 since it can induce cooperation with apoptosis and differentiation in response to autophagic signals , autophagy can be manipulated for a better therapy on acute myeloid leukemia .