Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou, Jianbiao; Chng, Wee‐Joo

doi:10.21037/sci.2017.01.06

Cited by 38 publications

(30 citation statements)

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“…Recent evidence has shown that aberrant splicing due to multiple mutations in the splicing pathway genes in myelodysplastic syndromes and AML constitutes an important pathophysiologic mechanism. [57][58][59][60] In the current study, the role of CDK9 in splicing was not fully evaluated, but future studies should address this. This would be particularly relevant, because CDK9 inhibition in both MDS and AML could potentially provide a unique therapeutic strategy to target aberrant splicing.…”

Section: Discussionmentioning

confidence: 92%

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Beauchamp

Abedin

Radecki

et al. 2019

Blood

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Aberrant activation of mTOR signaling in acute myeloid leukemia (AML) results in a survival advantage that promotes the malignant phenotype. To improve our understanding of factors that contribute to mammalian target of rapamycin (mTOR) signaling activation and identify novel therapeutic targets, we searched for unique interactors of mTOR complexes through proteomics analyses. We identify cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8. Our studies demonstrate that CDK9 is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to RAPTOR and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to RICTOR, SIN1, and mLST8, forming CTORC2, and controls messenger RNA (mRNA) translation through phosphorylation of LARP1 and rpS6. Pharmacological targeting of CTORC complexes results in suppression of growth of primitive human AML progenitors in vitro and elicits strong antileukemic responses in AML xenografts in vivo.

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Section: Discussionmentioning

confidence: 92%

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Beauchamp

Abedin

Radecki

et al. 2019

Blood

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“…The unlimited proliferation and evasion of apoptosis as well as differentiation arrested are characteristic of AML cells [ 33 , 34 ]. Deregulated signal transduction pathways, resulting from multiple genetic or epigenetic lesions, are believed to be the fundamental causes of the leukemogenesis [ 35 – 37 ]. Elevated expression of PRL-3 has been identified in about half of AML bone marrow samples and associated with poor outcome.…”

Section: Discussionmentioning

confidence: 99%

A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase

et al. 2018

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BackgroundProtein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor.MethodsIn this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism.ResultsThe list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/β-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/β-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG-001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/β-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells.ConclusionsIn summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/β-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0581-9) contains supplementary material, which is available to authorized users.

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“…More than 10 years ago, cancer stem cell (CSC) has been described as the origin of various cancers and is associated to disease progression [ 53 ]. These CSC populations are rare, and are functionally and phenotypically different form the bulk of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Tumor-derived exosomes in colorectal cancer progression and their clinical applications

Zhou

Chen

et al. 2017

Oncotarget

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Colorectal cancer (CRC) ranks as the third leading cause of cancer mortality in both of men and women worldwide due to its metastatic properties and resistance to current treatment. Recent studies have shown that tumor-derived exosomes play emerging roles in the development of cancer. Exosomes are nano-sized extracellular vesicles (EVs) that contain lipids, proteins, DNAs, and RNA species (mRNA, miRNA, long non-coding RNA). These exosomal cargos can be transferred locally and systemically, after taken by recipient cells, so exosomes represent a new form of intercellular communication. There is increasing evidence demonstrating that exosomes control a wide range of pathways bolstering tumor development, metastasis and drug resistance. This review provides an in-depth and timely summary of the role of exosomes in CRC. We first describe the common features and biogenesis of exosomes. We then highlight important findings that support the emerging roles of exosomes in CRC cell growth, invasion and metastasis, as well as resistance to treatment. Finally, we discuss the clinical application of exosomes as diagnostic biomarkers, in vivo drug delivery system and the potential of novel exosome-based immunotherapy for CRC.

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Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Cited by 38 publications

References 100 publications

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase

Tumor-derived exosomes in colorectal cancer progression and their clinical applications

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