Expression of autophagy genes in acute myeloid leukemia: associations with clinical characteristics and prognosis

Peng, Liang; Miao, Maohua; Liu, Z G; Hu, Rong; Jiang, Hao; Li, C; Y, S

doi:10.4149/neo_2018_171028n691

Cited by 10 publications

(9 citation statements)

References 18 publications

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“…RUBICON expression is significantly decreased in AML cases compared with control group 33 . Accordingly, an involvement of autophagy pathway in the outcome of AML leukemia has been suggested.…”

Section: Discussionmentioning

confidence: 81%

The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy

Marcos-Villar

Nieto

2019

Sci Rep

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Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.

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Section: Discussionmentioning

confidence: 81%

The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy

Marcos-Villar

Nieto

2019

Sci Rep

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“…In neoplastic cells however, autophagy sustains survival and proliferation upon exposure to intracellular and environmental stress, hence supporting tumor growth, invasion, and metastatic dissemination 6 . The deregulation of autophagy has been reported in AML [7][8][9][10] . Historical and new treatments have been shown to induce autophagy, which may be protective or participate in cell death depending on the compound [11][12][13][14] .…”

Section: Introductionmentioning

confidence: 97%

Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family that controls the canonical autophagy pathway and vesicular trafficking. Using a recently developed specific inhibitor (VPS34-IN1), we found that VPS34 inhibition induces apoptosis in AML cells but not in normal CD34+ hematopoietic cells. Complete and acute inhibition of VPS34 was required for the antileukemic activity of VPS34-IN1. This inhibitor also has pleiotropic effects against various cellular functions related to class III PI3K in AML cells that may explain their survival impairment. VPS34-IN1 inhibits basal and l-asparaginase-induced autophagy in AML cells. A synergistic cell death activity of this drug was also demonstrated. VPS34-IN1 was additionally found to impair vesicular trafficking and mTORC1 signaling. From an unbiased approach based on phosphoproteomic analysis, we identified that VPS34-IN1 specifically inhibits STAT5 phosphorylation downstream of FLT3-ITD signaling in AML. The identification of the mechanisms controlling FLT3-ITD signaling by VPS34 represents an important insight into the oncogenesis of AML and could lead to new therapeutic strategies.

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“…Unfortunately, this would result in only a few patients being enrolled in our study, and the statistical power could, therefore, be significantly reduced. Of note, Liang et al 43 also observed a trend toward higher ULK1 mRNA levels in the AML patients compared with the patients with benign hematological diseases. Subsequently, we centered on the molecular mechanism underlying ULK1 high expression in NPM1-mutated AML.…”

Section: Discussionmentioning

confidence: 89%

NPM1 mutant maintains ULK1 protein stability via TRAF6‐dependent ubiquitination to promote autophagic cell survival in leukemia

et al. 2020

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Nucleophosmin (NPM1) mutations are the most frequent genetic alteration in acute myeloid leukemia (AML) and aberrant cytoplasm-dislocated NPM1 mutant is a distinct biological characterization of this disease. Our group previously reported that NPM1 mutant elevated autophagy activity and autophagy activation contributed to leukemic cell survival. However, the molecular mechanisms by which cytoplasmic NPM1 mutant involving in the autophagy pathway has not been fully elucidated.Here, we showed that Unc-51-like kinase 1 (ULK1) as a core autophagy protein was highly expressed in NPM1-mA positive OCI-AML3 cells and primary NPM1mutated AML blasts. Meanwhile, we found that NPM1-mA could interact with ULK1 protein and positively regulated ULK1 protein levels. Mechanically, NPM1-mA promoted TRAF6-dependent K63 ubiquitination and further maintained ULK1 stability and kinase activity via miR-146a. In addition, ULK1 high expression-mediated autophagy activation and facilitated to leukemic cell proliferation. Finally, we demonstrated that restoring ULK1 expression, ULK1 inhibitor SBI-0206965 treatment and using shULK1 partially rescued the effect of NPM1-mA on autophagy and cell survival. In conclusion, our findings suggest that NPM1 mutant interacts with ULK1, and thus, maintains its protein stability, which is required for NPM1 mutant-mediated autophagic cell survival. These data extend our understanding of the functions of NPM1 mutant in the regulation of autophagy activation in NPM1-mutated AML.

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Expression of autophagy genes in acute myeloid leukemia: associations with clinical characteristics and prognosis

Cited by 10 publications

References 18 publications

The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy

The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy

Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia

NPM1 mutant maintains ULK1 protein stability via TRAF6‐dependent ubiquitination to promote autophagic cell survival in leukemia

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