ATRA and ATO team up against NPM1

Grant, Steven

doi:10.1182/blood-2015-04-636217

Cited by 5 publications

(3 citation statements)

References 10 publications

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“…NPM1 mutation results in cytoplasmic mislocalization of the mutant protein (NPM1c +), which is critical for its role in leukemogenesis [ 3 ]. To date, researchers have focused mainly on the effect of NPM1c + on functional interactions with its nuclear protein interacting partners and have tried to target NPM1c + by using CRM1 inhibitors or a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) [ 4 , 5 ]. Although most patients respond to the current therapy and achieve complete remission, relapse occurs frequently [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Jing

Jiang

et al. 2021

J Exp Clin Cancer Res

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Background Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms. However, the biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. Here, we aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML. Methods The expression of HOTAIRM1 was analyzed with a public database and further determined by qRT-PCR in NPM1-mutated AML samples and cell lines. The cause of upregulated HOTAIRM1 expression was investigated by luciferase reporter, chromatin immunoprecipitation and ubiquitination assays. The functional role of HOTAIRM1 in autophagy and proliferation was evaluated using western blot analysis, immunofluorescence staining, a Cell Counting Kit-8 (CCK-8) assay, a 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, flow cytometric analyses and animal studies. The action mechanism of HOTAIRM1 was explored through RNA fluorescence in situ hybridization, RNA pulldown and RNA immunoprecipitation assays. Results HOTAIRM1 was highly expressed in NPM1-mutated AML. High HOTAIRM1 expression was induced in part by mutant NPM1 via KLF5-dependent transcriptional regulation. Importantly, HOTAIRM1 promoted autophagy and proliferation both in vitro and in vivo. Mechanistic investigations demonstrated that nuclear HOTAIRM1 promoted EGR1 degradation by serving as a scaffold to facilitate MDM2-EGR1 complex formation, while cytoplasmic HOTAIRM1 acted as a sponge for miR-152-3p to increase ULK3 expression. Conclusions Taken together, our findings identify two oncogenic regulatory axes in NPM1-mutated AML centered on HOTAIRM1: one involving EGR1 and MDM2 in the nucleus and the other involving the miR-152-3p/ULK3 axis in the cytoplasm. Our study indicates that HOTAIRM1 may be a promising therapeutic target for this distinct leukemia subtype.

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Section: Introductionmentioning

confidence: 99%

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Jing

Jiang

et al. 2021

J Exp Clin Cancer Res

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“…NCL expression is not dependent on the presence of the NPM mutation [149]. It is also interesting to note that all-trans retinoid acid (ATRA), already described in relation to NPM [150,151], leads to a shift into G0/G1 phase and also a relocation of NPM, even if not restoring the interaction between NCL and NPM [149]. NCL seems to be an interesting target and is already proven to be responsive to oridonin, a direct inhibitor of NCL, potentially impairing its ability to stabilize specific mRNAs [152].…”

Section: Nucleolinmentioning

confidence: 95%

RNA-Binding Proteins in Acute Leukemias

Schuschel

Helwig

Hüttelmaier

et al. 2020

IJMS

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Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.

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“…This combination has been found to increase APL cell death and to reduce the number of bone marrow blasts through the induction of oxidative stress and interference with the translation of mutant oncoproteins [50, 51]. In this context, El Hajj et al [47] found that RA and ATO can synergistically trigger the proteasomal degradation of mutant nucleophosmin-1 (NPM1), the most frequently mutated protein in AML.…”

Section: Targeting Leukemia Stem Cellsmentioning

confidence: 99%

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

et al. 2016

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Background Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are characterized by high self-renewal and multi-lineage differentiation capacities. CSCs are thought to play indispensable roles in the initiation, progression and metastasis of many types of cancer. Leukemias are thought to be initiated and maintained by a specific sub-type of CSC, the leukemia stem cell (LSC). An important feature of LSCs is their resistance to standard therapy, which may lead to relapse. Increasing efforts are aimed at developing novel therapeutic strategies that selectively target LSCs, while sparing their normal counterparts and, thus, minimizing adverse treatment-associated side-effects. These LSC targeting therapies aim to eradicate LSCs through affecting mechanisms that control their survival, self-renewal, differentiation, proliferation and cell cycle progression. Some LSC targeting therapies have already been proven successful in pre-clinical studies and they are now being tested in clinical studies, mainly in combination with conventional treatment regimens. Conclusions A growing body of evidence indicates that the selective targeting of LSCs represents a promising approach to improve disease outcome. Beyond doubt, the CSC hypothesis has added a new dimension to the area of anticancer research, thereby paving the way for shaping a new trend in cancer therapy.

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ATRA and ATO team up against NPM1

Cited by 5 publications

References 10 publications

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

RNA-Binding Proteins in Acute Leukemias

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

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