Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia

J of Cellular Biochemistry

Fang

et al. 2018

Acute myeloid leukemia (AML) is a malignant clonal hematopoietic disease, which is caused by hematopoietic stem cell abnormalities. Epigenetic regulation, especially of microRNAs (miRNAs), mostly results from external or environmental effects and is critical to AML. In this study, for the first time, we report that decreased expression of miR‐345‐5p facilitates the proliferation of leukemia cells in AML. Further study demonstrated that AKT1/2 was the target of miR‐345‐5p and was responsible for the dysregulation of leukemia cell proliferation and apoptosis. Inhibition of AKT1/2 ameliorated this malignant effect, which provides new insight into AML diagnosis, treatment, prognosis, and next‐step translational investigations.

Section: Discussionmentioning

confidence: 70%

miR‐345‐5p regulates proliferation, cell cycle, and apoptosis of acute myeloid leukemia cells by targeting AKT2

Ying

J of Cellular Biochemistry

Fang

et al. 2018

“…Among these signaling cascades, mTOR signaling plays prominent roles (Tabe et al, 2017). In the present study, we report a natural monomer from Chinese medicinal herb Evodia rutaecarpa, dihydroevocarpine.…”

Section: Discussionmentioning

confidence: 76%

Targeting of mTORC1/2 by dihydroevocarpine induces cytotoxicity in acute myeloid leukemia

Xiong

Journal Cellular Physiology

et al. 2018

Interactions between the tumor cells and bone marrow (BM) microenvironment promote survival, growth, and chemoresistance of acute myeloid leukemia (AML). The mTOR pathway plays a key role in mediating the AML‐BM microenvironment interactions. Here, we report the anti‐AML activity of a natural monomer extracted from the Chinese medicinal herb Evodia rutaecarpa, dihydroevocarpine. Our results showed that dihydroevocarpine‐induced cytotoxicity, apoptosis, and G0/G1 arrest in AML cells, and inhibited the tumor growth in an AML xenograft model. Importantly, our study revealed that the dihydroevocarpine treatment inhibited the mTOR pathway via suppressing the mTORC1/2 activity, and thus overcame the protective effect of the BM microenvironment on AML cells. Taken together, our findings suggest that dihydroevocarpine could be used as a potential anti‐AML agent alone or a therapeutic adjunct in AML therapy, particularly in the presence of the BM microenvironment.

“…In addition, inhibiting mTOR using Rapamycin or Everolimus accelerates differentiation of APL cells (Jin et al, 2018;Isakson et al, 2010). While PI3K/AKT/mTOR pathways are activated in about 80% of AML cases, mTOR inhibitors had only modest effects in AML therapy (Mirabilii et al, 2018;Tabe et al, 2017). Furthermore, despite its role in leukemia cells, mTOR activity is crucial for hematopoietic stem cell (HSC) proliferation and self-renewal potential (Ghosh & Kapur, 2016).…”

Section: Discussionmentioning

confidence: 99%

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Humbert

Seiler

Mosimann

et al. 2020

Preprint

Switzerland 2 TRANSAUTOPHAGY: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138 Abstract Acute myeloid leukemia (AML) is a blood cancer characterized by a block in differentiation and increased survival of the resulting AML blast cells. While standard chemotherapy for AML cures only 30% of patients, differentiation-inducing therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide achieves 90% cure rates in acute promyelocytic leukemia (APL). A better understanding of the molecular mechanisms underlying ATRA therapy in APL may provide new perspectives in the treatment of additional AML subtypes.Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis. While FASN levels are very low in healthy adult tissues, it is often highly expressed in cancer cells, thus representing a potential therapeutic target. We found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34 + hematopoietic progenitors in two AML cohorts (n=68, n=203) (p<0.05). Accordingly, FASN levels decreased during ATRA-mediated granulocytic differentiation of APL cells, partially via autophagic degradation. Furthermore, our data suggests that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG), accelerates the differentiation of APL cell lines and significantly resensitized ATRA refractory non-APL AML cells. Decreasing FASN expression reduced mTOR activity and promoted translocation of transcription factor EB (TFEB) to the nucleus. Lysosomal biogenesis was activated, consistent with TFEB transcriptional activation of CLEAR network genes.Together, our data demonstrates that inhibiting FASN expression in combination with ATRA treatment promotes granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells. BioRXiv