Autophagy in Acute Myeloid Leukemia: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Ernestina Saulle
,
Isabella Spinello
,
Maria Teresa Quaranta
,
Catherine Labbaye

Autophagy is a highly conserved cellular degradation process that regulates cellular metabolism and homeostasis under normal and pathophysiological conditions. Autophagy and metabolism are linked in the hematopoietic system, playing a critical role in the self-renewal, survival and differentiation of hematopoietic stem and progenitor cells, and in cell death, particularly influencing the cell fate of the hematopoietic stem cell pool. In leukemia, autophagy supports leukemia cell growth, contributes to leukemia stem cell survival and resistance to chemotherapy. Acute myeloid leukemia (AML), a common type of acute leukemia with poor survival and prognosis, 

  • autophagy
  • hematopoiesis
  • acute myeloid leukemia
  • metabolism
  • therapy resistance

1. Autophagy and Acute Myeloid Leukemia Stem Cells

During leukemic development, LSCs can adapt their metabolism and autophagy mechanisms to supply high energy and nutrients required for LSCs proliferation and survival under conditions of nutrient deficiency, starvation, hypoxia, or during chemotherapy treatments [1][2][3][4][5].
Mitophagy, mitochondrial function, and integrity may affect the viability, proliferation, and differentiation potential and longevity of normal hematopoietic stem cells (HSCs) [6], and are important in the survival strategy of acute myeloid leukemia (AML) stem cells (LSCs).
In particular, the adenosine5′-monophosphate (AMP)-activated protein kinase (AMPK), a protein complex fundamental in mitochondrial metabolism and mitophagy, is constitutively activated in LSCs, increasing mitochondrial clearance to support LSCs growth and survival through its downstream target FIS1, the mitochondrial fission 1 protein component of a mitochondrial complex that promotes mitochondrial fission [7]. AMPK/FIS1-mediated mitophagy is required for the self-renewal and survival of LSCs [7]. An overexpression of FIS1 was also found in AML cells while FIS1 depletion impairs mitophagy, weakening the self-renewal capacity of LSCs and determining the induction of myeloid differentiation by GSK3 inactivation (glycogen synthase kinase 3), thus indicating mitophagy as being a regulatory mechanism for the progression of AML [7]. More recently, the loss of sequestosome 1 (SQSTM1), also known as p62, a selective autophagy receptor crucial for the development and progression of AML in vivo, induces the accumulation of damaged mitochondria and mitochondrial superoxide, thus compromising the survival of leukemia cells. Then, the loss of SQSTM1 impairs leukemia progression in AML mouse models, underlying the role of mitophagy in the survival of LSCs [8]. Altogether, these studies demonstrate that enhanced autophagic activity of LSCs is required for malignant progression into AML.
However, in contrast to the autophagy activation observed in AML, a loss of autophagy in healthy HSCs triggers the expansion of a population of progenitor cells in the bone marrow, giving rise to severe and invasive myeloproliferation, such as in human AML [9]. This apparent paradox can be explained by the distinct roles that autophagy can play during AML progression, which may be different at various stages of leukemogenesis [10][11]. Autophagy in normal HSCs may prevent the onset of cancer, as a tumor suppressive mechanism. Indeed, autophagy removes damaged organelles, such as mitochondria, and protects hematopoietic cells from genomic instability and inflammation, thus preventing the onset of leukemia. Particularly, increased DNA damage, high ROS levels, aneuploidy, and an aberrant accumulation of p62/SQSTM1 have been correlated with an impaired autophagic process, indicating a key role of autophagy in preventing tumor initiation [12]. Conversely, in established cancer, autophagy may function as a favorable pathway that promotes survival and tumor growth, by helping tumor cells to escape metabolic stress and death stimuli.
Some studies have also shown that the activation of autophagic flow plays a role only in the initiation of AML, with a transformation from HSCs to LSCs, and, therefore, after this phase, autophagy is not required for disease maintenance [13]. Studies in MLL-AF9 AML, the most common alteration in childhood AML, indicate ATG5 or ATG7 as necessary for the onset of AML, but once the leukemic condition is established, autophagy is not required for LSC function in vivo [13][14]. However, in a different MLL-ENL AML mouse model, Atg5 or Atg7 knockout reduced the number of functional LSCs, increased mitochondrial activation and ROS levels in these cells, and prolonged the survival of leukemic mice [15]. In this context, during the leukemogenesis process, histone methylation can regulate core autophagy effectors and upstream autophagic regulators such as ATG 5 and ATG7 to influence autophagy level indirectly [16]. Together, these studies suggest a highly complex and context-dependent role for autophagy in leukemic transformation with respect to the maintenance properties of LSCs in AML.
The dual role of autophagy in AML, as a promoter or suppressor of cancer in AML, is still a matter of debate. Studies have shown that autophagy can act as a pro or anti-proliferative mechanism depending on the lineage and the molecular genotypic context of the disease, reflecting the degree of heterogeneity of AML [17].

2. Regulation of Autophagy Genes in Acute Myeloid Leukemia Cells

Numerous studies have shown that increased autophagy in AML cells confers protection from chemotherapeutic treatment and promotes AML cell survival.
Increased ATG7-mediated autophagy has been associated with poor clinical outcomes and a short duration of remission in AML patients [18]. More recently, some proteins involved in leukemic cell survival, and overexpressed in AML, have been related to ATG overexpression, underlying the interplay between autophagy and protein overexpression promoting leukemic cell survival [19]. Hu et al. have shown that a high expression of SIRT1 (Sirtuin 1), a key player in mitochondrial biogenesis and autophagy-related protein, is associated with high CXCR4 expression, a negative prognostic marker in AML, and with other autophagy-related proteins such as ATG5 and LC3 in primary human AML samples, indicating a potential role of the SDF-1α-CXCR4 signaling pathway in autophagy induction in AML cells, which further promotes their survival under stress [20].
The transient receptor potential melastatin 2 (TRPM2) ion channel, involved in maintaining cell survival following oxidant injury, is highly expressed in AML [21]. By performing TRPM2-depletion, Chen SJ et al. [21] have shown that ULK1, Atg7, and Atg5 protein levels are decreased in TRPM2-depleted cells, leading to autophagy inhibition. Importantly, the depletion of TRPM2 in AML inhibits leukemia proliferation and increases the doxorubicin sensitivity of AML cells [21].
Functional studies in normal CD34+ CB cells indicated that the inhibition of VMP1 expression reduced autophagic flux, with decreased hematopoietic stem and progenitor cell (HSPC) expansion, delayed differentiation, increased apoptosis, and impaired cell function and in vivo engraftment. Similar results were observed in leukemic cell lines and primary AML CD34+ cells. Furthermore, ultrastructural analysis indicated that leukemic cells overexpressing VMP1 have a reduced number of mitochondrial structures, and the number of lysosomal-degrading structures has increased. VMP1 (vacuole membrane protein-1) overexpression increased autophagic flux and improved mitochondrial quality, which coincided with an increased threshold for venetoclax-induced loss of mitochondrial outer membrane permeabilization (MOMP) and apoptosis in leukemia cells [22].
Heterozygous deletions, missense mutations, or changes in the number of copies of key autophagy genes have been found with a high frequency in AML patients, especially AML patients with complex karyotypes [15][23]. In particular, a heterozygous chromosomal loss of 5q, 16q, or 17p correlates with regions encoding autophagy genes ATG10 and ATG12, GABARAPL2 and MAP1LC3B, or GABARAP, respectively [15], and several others autophagy genes have a low level of expression in human AML blasts, a decreased autophagic flow, and high levels of ROS [15]. In addition, a study suggested that key autophagy genes such as ULK1, ATG3, ATG4D, and ATG5 were significantly downregulated in primary AML cells compared to normal granulocytes [24].

3. Autophagic Biomarkers

Significant progress has recently been made to identify specific autophagy-related genes for the prediction of clinical outcomes in AML. Along with the ATG genes previously described, several microRNAs implicated in leukemogenesis and chemoresistance have been also involved in the activation of autophagy, and may be used as biomarkers [25]. In particular, miR-17-5p overexpression in leukemia promotes AML proliferation by inhibiting autophagy through BECN1 targeting [26][27][28]. Ganesan et al. demonstrated that stromal cells downregulate miR-23a-5p levels in leukemic cells, leading to the upregulation of protective autophagy in these cells, thereby increasing their resistance to chemotherapy toxicity [29]. MiR-143 overexpression was shown to enhance the sensitivity of AML cells to the cytotoxicity of cytarabine (Ara-C) treatment by inhibiting autophagy through ATG7 and ATG2B targeting [30]. An overexpression of miR-15a-5p is involved in the chemoresistance of AML patients, through autophagy-related genes ATG9A, ATG14, GABARAPL1, and SMPD1 targeting AML cells [31].
Recent advances in bioinformatics have yielded an autophagy-related signature that can help to predict overall survival (OS) and/or the clinical outcomes of AML patients. Several studies have shown that the progression of AML depends on the autophagy-associated gene signature [32]. A recent bioinformatics study has built a model containing 10 autophagy-related genes to predict the survival of AML patients, showing that groups at high risk of AML have an increased expression of immune checkpoint genes and a higher percentage of CD4 T and NK cells [33]. In addition, this research was able to predict OS in AML through the signature of 10 genes, indicating this model as an effective prognostic predictor for AML patients, useful to guide patient stratification for immunotherapies and drugs [33]. The bioinformatics study LASSO Cox regression that identified a critical risk signature for AML, consisting of the autophagy genes BAG3, CALCOCO2, CAMKK2, CANX, DAPK1, P4HB, TSC2, and ULK1, had excellent predictive power for AML prognosis [34]. Notably, the immunosuppressive cytokines were found to be significantly increased in the tumor microenvironment of patients with a high-risk of AML, predicted on the basis of the autophagy-related signature of these patients [34]. However, the prognostic value of the ATG signature in the clinical setting is still debated. Therefore, the roles of the ATG signature and autophagy in the pathogenesis of AML should be further investigated.
Furthermore, an interesting study indicated that an autophagy-related lncRNA signature containing six lncRNAs (HYMAI, MIR155HG, MGC12916, DIRC3, C1orf220, and HCP5) may have an important prognostic value [35]. A recent study indicated four autophagy-associated lncRNAs (MIR133A1HG, AL359715.1, MIRLET7BHG, and AL356752.1) as a signature to potentially use as a biomarker to predict the survival of AML patients [36].
Collectively, these data indicate that the role of autophagy in tumor development clearly depends on the type of AML and stage of tumor development. Furthermore, autophagy may provide cancer cells with a survival strategy, suggesting a therapeutic use for autophagy inhibition. On the other hand, autophagy can induce cell death, pointing to autophagy activation as a novel strategy in cancer therapy. Therefore, it is necessary to determine the role played by autophagy in the molecular subtypes of AML, or the degree of tumor development, to verify whether its modulation could lead to benefits for the treated patient.

4. Autophagy and Genetic Alterations in Acute Myeloid Leukemia

The AML phenotype results from multiple molecular, genetic, and epigenetic alterations affecting the differentiation, proliferation, and apoptosis of myeloid progenitors. The World Health Organization has classified AMLs according to the presence of particular genetic alterations, frequently originating from chromosomal translocations or other genome rearrangements such as t(8;21), t(15;17), inv (16), inv(3), t(6;9), t(9;11) or t(11;19), or mutations in receptor kinases, in key signaling mediators, proto-oncogenes, or epigenetic enzymes, e.g., mutations in FLT3 (FMS-like tyrosine kinase 3), TP53, c-KIT or IDH1/2, NPM1 (nucleophosmin 1), and CCAAT enhancer-binding protein (CEBPA) [37][38][39]. These mutations in AMLs have an impact on the choice of the most suitable therapy.
The association between autophagy and recurrent genetic alterations has been described in several studies in AML, but needs further investigation [40][41]. Here, researchers summarize and update the recent advances that have highlighted the link between autophagy and fusion genes and recurrent oncogenic mutations in AML and the involvement of autophagy in chemotherapy treatment (Figure 1).
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Figure 1. Gene mutations in AML and autophagy. Several recurrent genetic abnormalities in AML are involved in the deregulation of autophagy, leading to leukemia progression.

4.1. Fusion Genes in Acute Myeloid Leukemia and Autophagy

Most cases of APL are caused by a de novo t (15;17) (q22; q21) translocation, which results in the fusion of the RARA gene with the PML gene [42][43]. APL cells that have a lower expression of autophagy-related genes than normal cells have a reduced autophagic activity. By using differentiating agents, such as all-trans retinoid acid (ATRA) and arsenic trioxide (ATO) currently used in clinical settings, the expression level of autophagy-related genes increases, thus restoring autophagy in APL cells [44]. Both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). In addition, mTOR-dependent autophagic action is required for ATO-induced NETosis in APL cells [45]. Of note, rapamycin, the inhibitor of mTOR pathway, synergizes with ATO in the eradication of leukemia-initiating cells (LIC) through the activation of NETosis in both APL cells and an in vivo APL model [45].
Mixed lineage leukemia (MLL) gene translocations 11q23 were observed in approximately 80% of pediatric AML. In these, the MLL gene can, by genomic translocation, be fused with >60 different fusion partners [46]. Treatment with the RAS oncogene inhibitor, tipifamib, leads to the inhibition of AML with the t(6;11) translocation by inducing both apoptosis and autophagy [47]. Another study demonstrated that ATG5 participates in the development of MLL-AF9-driven leukemia, but not in AML-sensitive chemotherapy mice expressing MLL-AF9 [48].
Acute myeloid leukemia with core binding factor (CBF-AML) is characterized by the presence of t(8;21) (q22; q22), or inv (16) (p13q22)/t(16;16), which leads to the formation of RUNX1/RUNX1T1 (AML1/ETO) and CBFbeta-MYH11, respectively [49]. The activation of ULK1-mediated autophagy may control and delay AML1-ETO9a -guided leukemogenesis in an AML CASPASE-3 knockout mouse model [50], suggesting that CASPASE-3 is an important regulator of autophagy in AML. The results of these studies highlight the different roles of autophagy in the initiation, progression, and chemotherapeutic responses in AML cells, depending on the different type of aberrant oncoprotein.

4.2. Gene Mutations in Acute Myeloid Leukemia and Autophagy

FLT3
Among the most common genetic alterations in AML, the tyrosine kinase 3 (FLT3) gene mutation occurs in approximately 30% of AML cases.
The most frequent aberrations affecting FLT3 gene, associated with a poor prognosis in AML, are the internal tandem duplication (FLT3-ITD) in the juxtamembrane domain, and point mutations, involving the tyrosine kinase domain of FLT3 (FLT3-TKD) [51]. FLT3-ITD expression increases basal autophagy in AML cells through a mechanism involving transcription factor ATF4 (activating transcription factor 4) [52]. In addition, the inhibition of autophagy in FLT3-TKD cells, which are resistant to the FLT3 inhibitor quizartinib (AC220), also inhibits proliferation both in vitro and in vivo [52]. More recently, the acquired D835Y mutation induced resistance to the FLT3 inhibitor sorafenib, and activated autophagy in FLT3-ITD-positive cell lines. By inhibiting autophagy, the authors were able to overcome resistance to sorafenib in FLT3-ITD-positive AML, improving its efficacy [53]. Recently, a study showed that the inhibition of autophagy reduces the repopulation potential of FLT3-ITD AML LSCs associated with mitochondrial accumulation [54]. In addition, the authors showed that autophagy inhibition improves p53 activity and increases the TKI-mediated inhibition of AML progenitors [54].
Autophagy not only contributes to downstream proliferation of the FLT3-ITD receptor, but may also be involved in mutated receptor degradation. In fact, in one study, the frequent activation of the receptor tyrosine kinase RET was observed in several AML subtypes [55]. RET mediates autophagy suppression in an mTORC1-dependent manner, leading to the stabilization of the mutant FLT3 receptor. The genetic or pharmacological inhibition of RET decreased the growth of FLT3-dependent AML cells, with the upregulation of autophagy and FLT3 depletion [55]. These results suggest that restoring autophagy in FLT3-dependent AML may result in the degradation of mutated FLT3, and therefore may represent an interesting therapeutic approach. It has also been shown that the inhibition of the FLT3-ITD protein leads to an increase in ceramide synthesis and mediates ceramide-dependent mitophagy, leading to AML cell death [56][57].
KIT
KIT mutations are associated with an increased proliferation of leukemic cells and an increased risk of AML recurrence [58][59]. A recent study reported that the KIT D816V mutation in AML cells increases basal autophagy, stimulating AML cell proliferation and survival via STAT3 signaling [60]. A different point mutation in c-KIT (N822K T > A) constitutively activates this receptor, making AML cells highly sensitive to sunitinib (a tyrosine kinase inhibitor), resulting in AML cell death through the activation of both apoptosis and autophagy processes [61].
NPM1
Mutations in NPM1 (nucleophosmin 1) are the most frequent genetic alterations in adult AML, responsible for the aberrant localization of the NPM1 protein in the cytoplasm [62]. Increased autophagic activity found in NPM1 -mutated AML cells is involved in leukemic cell survival [63]. Mutant NPM1 can also interact with the tumor suppressor protein PML (leukemia pro-myelocytic protein), leading to PML delocalization and stabilization that, in turn, can activate autophagy via AKT signaling [63]. In another study, it was shown that in AML patients carrying mutant NPM1, the glycolytic enzyme PKM2 (pyruvate kinase M2) induced autophagy via phosphorylation of the autophagic protein Beclin 1, contributing to cell survival [64]. Finally, the NPM1 mutant protein can also interact with the autophagic protein ULK1, stimulating the TRAF6-dependent ubiquitination of ULK1 via miR-146, thereby maintaining ULK1 stability and functionality and promoting autophagic cell survival [65]. Furthermore, it was observed that the expression of RASGRP3, a protein associated with tumor progression, is upregulated in patients with AML with NPM1 mutation compared to patients with AML without mutant NPM1. The authors demonstrated that NPM1 -mut blocks the degradation of the RASGRP3 protein through binding to the ubiquitin ligase E3 MID1 protein, leading to RASGRP3 overexpression, as well as promoting the downstream activation of EGFR-STAT3, which in turn promoted proliferation and autophagy in AML cells [66].
P53
Alterations in the tumor suppressor gene TP53 are found in about 5–15% of AML cases, and, frequently, in older patients [67][68]. It has been proposed that the role of autophagy in the development of AML can be determined by the status of TP53. For wild-type TP53 AML, researchers have shown that pharmacological autophagy blockade achieves therapeutic benefits, while AMLs harboring TP53 mutations do not respond to the inhibition of autophagy by hydroxychloroquine (HCQ) [69][70]. The use of autophagic inhibitors may be a potential therapeutic strategy to use, particularly for the treatment of TP53 wild-type AML. For AML with TP53 mutations, autophagic pathways may be a therapeutic option to use for the elimination of mutant T TP53.
Another study demonstrated that macroautophagy stimulation by 17-AAG, a HSP90 inhibitor, causes the degradation of TP53 R248Q in AML cells and also enhances the transcription of autophagy-associated genes [71]. In addition, accumulated evidence indicates that TP53 activated by a variety of cellular stresses can trigger autophagy through the transactivation of pro-autophagy genes, including DRAM1 (autophagic modulator regulated by DNA damage 1), SESN1 (sestrin 1), and (sestrin SESN2) [71][72][73][74].
A recent study highlighted the role of autophagy in AML cells, in the context of p53-mediated apoptosis, which is associated with increased cytotoxicity to treatment with MDM2 inhibitors and Ara-C when miR-10a is inhibited [75]. The antileukemic strategy based on the use of MDM2/X inhibitors in wild-type p53 tumors to restore the normal and active conformation of p53, MDM2, and MDMX has not been extensively tested [76]. Thus, the use of a combination of treatments, including MDM2 inhibitors with autophagic modulators, may be a new strategy to improve the treatment of wild-type p53 AML.
Pharmacological treatments that modulate autophagy in AML patients carrying p53 mutations participate in the degradation of aberrant p53 proteins. The point mutation of TP53 at the amino acid residue R428 (R248Q), with gain-of-function activity, gives rise to malignant activity in lung cancer cells [77] and a loss of tumor suppressor function in AML [78].
Interestingly, the treatment with the Hsp90 inhibitor (17-AAG) results in the activation of chaperone-mediated autophagy, which induces the degradation of the aberrant protein p53R248Q in AML cells. In particular, under conditions of metabolic stress, 17-AAG induces the interaction between p53R248Q and the chaperone protein Hsc70, triggering chaperone-mediated autophagy to degrade p53R248Q [71]. These data open new opportunities for future studies that may elucidate the functional involvement of different types of autophagy and their connection with molecular mechanisms to improve anticancer therapies against AML harboring the different TP53 variants.
IDH1/2 (isocitrate dehydrogenase)
Recent advances in bioinformatics have enabled the identification of several epigenetic mutations affecting AML, including IDH1/2, Tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3A (DNMT3A), and ASXL1, all of which are associated with the pathogenesis of AML [79][80][81]. IDH proteins are isocitrate dehydrogenases, implicated in various biological processes, such as energy metabolism, histone demethylation, DNA modification, and adaptation to hypoxia. Further studies are needed to investigate innovative therapies based on targeted autophagy in combination with DNA hypomethylation to treat AMLs harboring certain types of epigenetic alterations.
DNMT3A
Mutations in the DNMT3A gene, an enzyme involved in the methylation of CpG dinucleotides, are present in 20–23% of adult patients with de novo AML [81]. Several studies have shown that the treatment of AML patients with DNA methyltransferase inhibiting agents, such as azacitidine (5-aza-2′-deoxycytidine), induces autophagic activity in AML leukemia cells [82]. A study performed on a DNMT3A R878H conditional knock-in mouse model, used to predict the specific long non-coding RNAs (lncRNAs) regulated by DNMT3A mutations in AML, first identified 23 differentially expressed lncRNAs, then the downstream target genes regulated by these lncRNAs, including ATP6V1A, a critical autophagy-related gene, the overexpression of which is associated with poor prognosis in AML [83]. However, there is still little evidence of a direct involvement of DNMT3A gene mutations with autophagic activity in AML.
Further studies are needed to understand the functional significance of autophagy associated with different genetic mutations in AML cells.

This entry is adapted from the peer-reviewed paper 10.3390/cells12111553

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