Autophagy in Acute Myeloid Leukemia: Comparison
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Please note this is a comparison between Version 6 by Jessie Wu and Version 5 by Ernestina Saulle.

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 MLyeloid Leukemia Stem Cells

During leukemic development, LSCs can adapt their metabolism and autophagicy mechanisms to provide thesupply high energy and nutrients required for LSCs proliferation and survival under conditions of nutrient deficiency, starvation, hypoxia, or during chemotherapy treatments [7 , 91 , 92 , 93 , 94 ] [1][2][3][4][5]. Mitophagy, mitochondrial function, and integrity canmay affect the viability, proliferation, and differentiation potential and longevity of normal hematopoietic stem cells (HSCs) [95][6], and are important in the survival strategy ofof acute myeloid leukemia (AML) stem cells (LSCs). In .
Specifartically,ular, the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), a protein complex criticfundamental 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 [ 96 ][7]. AMPK/FIS1-mediated mitophagy is required for LSCthe self-renewal and survival [of LSCs 96][7]. OAn overexpression of FIS1 was also found in AML cells while FIS1 depletion of FIS1 impairs mitophagy, weakening the self-renewal capacity of LSCs and resulting indetermining the induction of myeloid differentiation by GSK3 inactivation of GSK3 (glycogen synthase kinase 3), thus pointing toindicating mitophagy as being a regulatory mechanism for AMLthe progression [of 96AML ][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, therebyus compromising cellthe survival. of leukemia cells. Thusen, the loss of SQSTM1 impairs leukemia progression in AML mouse models of AML, underscorlying the role of mitophagy in LSCthe survival. of 97LSCs ][8]. CAltollectivelygether, these studies demonstrate that increaseenhanced autophagic activity of LSCs is required for malignant progression into AML. However, in contrast to the autophagy activation of autophagy observed in AML, a loss of autophagy in healthy HSCs triggers the expansion of a population of progenitor cells in the bone marrow, resulting ingiving rise to severe and invasive myeloproliferation, such as in human AML [ 53 ] [9]. This apparent paradox mcayn be explained by the distinct roles that autophagy maycan play during AML progression, which may be different at various stages of leukemogenesis [ 98 , 99][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. NoPartabicularly, increased DNA damage, high ROS levels, aneuploidy, and an aberrant accumulation of p62/SQSTM1 have been correlated with an impaired autophagyic process, indicating a key role of autophagy in preventing theumor initiation of tumor [100 ] [12]. Conversely, in established cancer, autophagy may function as a favorable pathway that promotes tumor survival and tumor growth,
by helping tumor cells to escape metabolic stress and death stimuli. Some studies have also shown that the activation of the autophagic flux onlyow plays a role only in the initiation of AML, with a transformation from HSCs to LSCs, and, therefore, after this stagphase, autophagy is not required for disease maintenance [101 ] [13]. AML sStudies in MLL-AF9 AML, the most common alteration in childhood AML, point to indicate ATG5 or ATG7 as requirednecessary for the onset of AML, but once the leukemic condition is established, autophagy is not required for LSC function LSC in vivo [101 , 102 ] [13][14]. However, in a different AML MLL-ENL AML mouse model, Atg5 or Atg7 knockout reduced the number of functional LSCs, increased thmitochondrial activation and ROS levels in these cells, and prolonged the survival of leukemic mice. ] [15]. In this context, during the process of leukemogenesis process, histone methylation can regulate centralore autophagicy effectors and upstream autophagic regulators such as ATG 5 and ATG7 to indirectly affect the level of fluence autophagy [104level ]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 demshonstratedwn 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 [105 ] [17].

2. Regulation of aAutophagy gGenes in AML ccute Myeloid Leukemia Cells

Numerous studies have demshonstratedwn that increased autophagy in AML cells confers protection from chemotherapyeutic 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 [ 106 ][18]. More recently, some proteins involved in leukemiac cell survival, and overexpressed in AML, have been related to ATG overexpression, underlying the interplay between autophagy and protein overexpression that promotesing leukemiac cell survival [8] .][19]. Hu et al. dhavemonstrated shown that elevateda high expression of SIRT1 (Sirtuin 1), a key player in mitochondrial biogenesis and autophagy-related protein, is associated with elevatedhigh CXCR4 expression of CXCR4, a negative prognostic marker in AML, and with other proteins reautophagy-related to autophagyproteins such as ATG5 and LC3 in primary human AML samples, indicating a potential role of the SDF-1α-CXCR4 signaling pathway in theautophagy induction of autophagy in AML cells, which further promotes their survival under stress [107 ] [20]. The transient receptor potential melastatin receptor 2 (TRPM2) ion channel, involved in the maintenance of maintaining cell survival afterfollowing oxidative damagent injury, is highly expressed in AML [[21]. 108By ].performing By performing TRPM2 -depletion , Chen SJ et al. [[21] 108have ] demshonstratedwn that the levels of ULK1, Atg7, and Atg5 protein levels are decreased in TRPM2- -depleted cells , leading to autophagy inhibition of autophagy. Importantly, TRPM2the depletion of TRPM2 in AML inhibits leukemia proliferation and increases the doxorubicin sensitivity of AML cells [ 108 ][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 cellularll function and in vivo engraftment in vivo. Similar results were observed in leukemic cell lines and primary AML CD34+ AML cells. Furthermore, ultrastructural analysis indicated that leukemic cells overexpressing VMP1 have a reduced number of mitochondrial structures, and the number of lysosomal -degradationing structures ihas increased. Overexpression of VMP1 (vacuole membrane protein-1) inoverexpression increased autophagic flux and improved mitochondrial quality,109 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 copythe number of copies of key autophagy genes have been found with a high frequency in AML patients, particularly inespecially AML patients with complex karyotypes [5 , 103 ] [15][23]. In particular, a heterozygous chromosomal loss of 5q, 16q, or 17p correlates with regions encoding the autophagicy genes ATG10 and ATG12 , GABARAPL2 , and MAP1LC3B, or GABARAP , respectively [ 103 ][15], and mseveranyl others autophagicy genes have a low level of expression in the Hhuman AML blasts, a reducdecreased autophagic fluxow, and high levels of ROS [[15]. 103].In Furaddithermore, oneion, 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 [ 110 ][24].

3. Autophagic bBiomarkers

Significant progress has recently been made to identify specific autophagy-related genes for the prediction of clinical outcomes in AML. Along with the Along with the previously described ATG genes previously described, several microRNAs implicated in leukemogenesis and chemoresistance have also been been also involved in autophagythe activation and canof autophagy, and may be used as biomarkers [[25]. 111In ]. Nopartablyicular, miR-17-5p overexpression in leukemia promotes AML proliferation by inhibiting autophagy through BECN1 targeting [ 112 , 113 , 114][26][27][28]. Ganesan et al. demonstrated that stromal cells downregulate miR-23a-5p levels in leukemiac cells, leading to the upregulation of protective autophagy in these cells, thereby increasing their resistance to chemotherapy toxicity [29]. 115MiR-143 ]. Ooverexpression of MiR-143 has been was shown to enhance the sensitivity of AML cells to the cytotoxicity of cytarabine (Ara-C) treatment by inhibiting autophagy through targeting ATG7 and ATG2B [116targeting ] [30]. An overexpression of miR-15a-5p is involved in the chemoresistance of AML patients, through the autophagy-related genes ATG9A , ATG14 , GABARAPL1, and SMPD1which targeting AML cells [ 117 ][31]. Recent advances in bioinformatics have yielded an autophagy-related signature that mcay helpn help to predict overall survival (OS) and/or the clinical outcomes of AML patients with AML. Several studies have shown that the progression of AML depends on the gene signature autophagy-associated with autophagygene signature [ 118 ][32]. A recent bioinformatics study conhastructed built a model containing 10 autophagy-related genes to predict the survival of AML patients, demonstratshowing that groups at high AML risk have higherrisk of AML have an increased expression of immune checkpoint genes and a higher percentage of CD4 T and NK cells [119][33]. .].In Furaddithermoreion, this study research was able to predict OS in AML through the signature of 10 genes, poinindicating to this model as an effective prognostic predictor for AML patients, useful to guide patient stratification for immunotherapies and medicationdrugs [119] . [33]. The LASSO Cox bioinformatics study LASSO Cox regression study whichthat identified a critical risk signature for AML, consisting of the autophagicy genes BAG3 , CALCOCO2 , CAMKK2 , CANX , DAPK1 , P4HB , TSC2, and ULK1 , had excellent predictive power for AML prognosis [ 120][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 [120 ] [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 [ 121 ][35]. A recent study pointed to dicated four autophagy-associated lncRNAs ( MIR133A1HG , AL359715.1 , MIRLET7BHG , and AL356752.1 ) as a signatures to potentially be used use as a biomarker to predict the survival of AML patients [ 122 ][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 gGenetic aAlterations in AMcute Myeloid Leukemia

The AML phenotype results from multiple molecular, genetic, and epigenetic alterations that affectffecting the differentiation, proliferation, and apoptosis of myeloid progenitors. The World Health Organization has classified AMLs based onaccording to the presence of particular genetic alterations, oftenfrequently originating from chromosomal translocations or other genome rearrangements such as t(8;21), t(15;17), inv (16), inv (3) (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, for examplee.g., mutations in FLT3 (FMS - -like tyrosine kinase 3), TP53 , c-KIT or IDH1/2 , NPM1 (nucleophosmin 1), and CCAAT enhancer -binding protein ( CEBPA ) [ 1 , 2 , 123 ][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 AML studies in AML, but needs further investigation [ 124 , 125 ][40][41]. Here, wresearchers 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 ).
Cell 12 01553 g002 550
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 AML and autophagy

4.1. Fusion Genes in Acute Myeloid Leukemia and Autophagy

Most cases of APL are caused by a de novo translocation t (15;17)(q22;q21), (q22; q21) translocation, which resultings in the fusion of the RARA gene with the PML gene [ 126 , 127 ][42][43]. APL cells that have a lower expression of autophagy-related genes than normal cells have a reduced autophagic activity. By Using differenusing differentiating agents, such as all-tiating 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 [ 128][44]. Both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). FurthermoreIn addition, mTOR-dependent autophagic action is required for ATO-induced NETosis in APL cells [ 129 ][45]. Of note, rapamycin, the inhibitor of the 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 [129 ] [45].
Translocat Mions of the mixed lineage leukemia ( MLL) gene )translocations 11q23 gene awere observed in approximately 80% of pediatric AMLs.. In these, the In these, the MLL gene can, by genomic translocation, be fused with >60 different fusion partners [ 130 ][46]. Treatment with the RAS oncogene inhibitor, tipifamib, leads to the inhibition of AML bywith the t(6;11) translocation by inducing both apoptosis and autophagy [ 131 ][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 [ 132 ][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), leadingwhich leads to the formation of RUNX1/RUNX1T1 (AML1/ETO) and CBFbeta-MYH11 , respectively [49]. The [activation of ULK1-mediated autophagy may control 133and ].delay ULK1-mediated activation of autophagy can control and delay AML1-ETO9a- -guidrivened leukemogenesis in an AML CASPASE-3 knockout mouse model [ 134][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 chemotherapyeutic responses in AML cells, depending on the different type of aberrant oncoprotein.

4.2. Gene mutations in AML and autophagy

4.2. Gene Mutations in Acute Myeloid Leukemia and Autophagy

  • FLT3
FLT3 Among the most common genetic alterations in AML, mutation of the tyrosine kinase 3 ( FLT3 ) gene omutation occurs in approximately 30% of AML cases. The most frequent aberrations affecting the 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) [ 135 ][51]. Expression of FLT3 -ITD inexpression increases basal autophagy in AML cells through a mechanism involving the transcription factor ATF4 (activating transcription factor 4) [[52]. 136In ]. Furaddithermoreion, the inhibition of autophagy in FLT3 cells-TKD cells, which are resistant to the FLT3 inhibitor quizartinib (AC220), also inhibits proliferation both in vitro and in vivo [ 136 ][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 sorafenib reresistance ito sorafenib in FLT3 -ITD-positive AML, improving its efficacy [ 137 ][53]. Recently, a study demshonstratwed that the inhibition of autophagy reduces the repopulation potential of FLT3-ITD AML LSCs associated with mitochondrial storage-associatedccumulation FLT3 -ITD AML LSCs [ 138][54]. In Furthermoreaddition, the authors demonstratshowed that autophagy inhibition enhanceimproves p53 activity and enhancesincreases the TKI-mediated inhibition of AML progenitors [ 138 ][54]. Autophagy not only contributes to the downstream proliferation of the FLT3-ITD receptor, but may also be involved in the degradation of the mutated receptor. Indeed degradation. In fact, in one study, the frequent activation of the RET receptor tyrosine kinase RET was observed in differentseveral AML subtypes of AML [ 139 ][55]. RET mediates autheophagy suppression of autophagy in an mTORC1-dependent manner, leading to the stabilization of the mutant FLT3 receptor. GThe genetic or pharmacological inhibition of RET reducdecreased the growth of FLT3-dependent AML cells, with the upregulation of autophagy and FLT3 depletion of FLT3 [ 139][55]. These results suggest that restoration of ng autophagy in FLT3-dependent AML may result in the degradation of mutant FLT3ted FLT3, and thuserefore may represent an attractiveinteresting therapeutic approach. Inhit has also been shown that the inhibition of the FLT3-ITD protein has also been shown to lead to leads to an increased in ceramide synthesis and mediates ceramide-dependent mitophagy, leading to AML cell death [140 , 141 ] [56][57].
  • KIT
Mutations in KIT KIT mutations are associated with an increased leukemia cell proliferation of leukemic cells and an increased risk of AML recurrence [ 142 , 143 ][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 [ 144 ][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 autophagicy processes [ 145 ][61].
  • NPM1
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 146found ].in The increased autophagic activity found in NPM1 -mutated AML cells is involved in leukemic cell survival [ 147 ][63]. TheMutant NPM1 mutant can also interact with the tumor suppressor protein PML (leukemia pro-myelocytic protein), leading to thePML delocalization and stabilization of PML whichthat, in turn, can activate autophagy via AKT signaling [147 ] [63]. In another study, it was shown that in AML patients carrying the mutant NPM1 , the glycolytic enzyme PKM2 (pyruvate kinase M2) induced autophagy throughvia phosphorylation of the autophagic protein Beclin 1, contributing to cell survival [ 148 ][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 [149 ] [65]. Furthermore, ith was observed that the expression of RASGRP3, a protein associated with tumor progression, was observed to be is upregulated in AML patients with AML with NPM1 mutation compared to AML patients with AML without mutant NPM1 . . The authors demonstrated that NPM1 -mut blocks the degradation of the RASGRP3 protein through binding to the E3 ubiquitin ligase E3 MID1 protein, leading to RASGRP3 overexpression of RASGRP3, as well as promoting the downstream activation of EGFR-STAT3, which in turn promotesd proliferation and autophagy in AML cells [150 ] [66].
  • P53
P53 Alterations ofin the tumor suppressor gene TP53 are found in apprboximately 5-ut 5–15% of AML cases and, and, frequently, in older patients [67][68]. It has been proposed that [the role of autophagy in the development of AML 151can ,be 152determined ].by It has been proposed that the role of autophagy in the development of AML may be determined by TP53the status of TP53. For wild-type AML TP53 AML, researchers demonstratedhave shown that pharmacological blockade of aautophagy blockade achieves therapeutic benefits, whereasile AMLs harboring TP53 mutations faildo tonot respond to autophagythe inhibition of autophagy by hydroxychloroquine (HCQ) [ 153 , 154][69][70]. The use of autophagic inhibitors may be a potential therapeutic strategy to use, particularly for the treatment of TP53 wild-type TP53 AML. For AML with TP53 mutations , autophagic pathways may be a therapeutic option to be useduse for the elimination of the TP53 T mutant T TP53. Another study demonstrated that stimulation of maacroautophagy stimulation by 17-AAG, an HSP90 inhibitor, results in causes the degradation of TP53 R248Q in AML cells and also enhances the transcription of autophagy-associated genes [155[71]. ]In . Furaddithermoreion, accumulatinged evidence indicates that TP53 activated by a variety of cellular stresses can trigger autophagy through the transactivation of pro-autophagicy genes, including DRAM1 ((autophagic DNA modamageulator regulated autophagy modulatorby DNA damage 1), SESN1 (sestrin 1), and ( sestrin SESN2 ) [ 155 , 156 , 157 , 158 ][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 [159 ] [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 [160 ] [76]. Thereforeus, the use of a combination of treatments, including MDM2 inhibitors with autophagic modulators, couldmay be a novelew 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. PThe 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] 161 ] and a loss of tumor suppressor function in AML [ 162 ][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. NotablyIn 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 [ 155 ][71]. These data open new opportunities for future studies that couldmay elucidate the functional involvement of different types of autophagy and their connection with the molecular mechanisms forto improvinge anticancer therapies against AML harboring the different TP53 variants .
  • IDH1/2 (isocitrate dehydrogenase)
. 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 [ 163 , 164 , 165][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 Mutations in the DNMT3A gene , an enzyme involved in the methylation of CpG dinucleotide methylations, are present in 20-–23% of adult patients with de novo AML [ 165 ][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 [166 ] [82]. A study iperformed 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 lncRNAsdifferentially 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 167involvement ].of However, there is still little evidence for 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.

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