Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia

Yeh, Yuh Ying; Chen, Rong; Hessler, Joshua; Mahoney, Emilia; Lehman, Amy; Heerema, Nyla A.; Grever, Michael R.; Plunkett, William; Byrd, John C.; Johnson, Amy J.

doi:10.18632/oncotarget.2096

Cited by 40 publications

(38 citation statements)

References 55 publications

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“…com/en-us/product/dc-protein-assay) as previously described. 41 Twenty-five micrograms lysate was resolved on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to the polyvinylidene fluoride (PVDF) membrane, and blotted with specific primary and secondary antibodies (Sigma-Aldrich) accordingly. Primary antibodies used for immunoblotting for CD63 (H-193) and CD9 (C-4) were purchased from Santa Cruz Biotechnology (Dallas, TX).…”

Section: Immunoblottingmentioning

confidence: 99%

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Yeh¹,

Özer²,

Lehman³

et al. 2015

Blood

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139

152

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Key Points• CLL exosomes exhibit a disease-relevant microRNA signature.• B-cell receptor signaling enhances exosome secretion in CLL that can be antagonized by ibrutinib.Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by a-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes a-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile. (Blood. 2015;125(21):3297-3305) IntroductionChronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western world and remains incurable with current therapies. Understanding the different contributors to pathogenesis in CLL represents a path by which improved therapeutic options can be proposed. Although the pathogenesis of CLL for many years has been attributed to defective apoptosis of tumor cells, robust death is typically noted when these are removed from the body, suggesting a strong role of nurturing in the tumor microenvironment.1 In vivo, CLL cells reside in close contact with T lymphocytes, stromal cells, monocyte-derived nurse-like cells, follicular dendritic cells, and macrophages, collectively referred to as the "microenvironment." Interactions between these components result in CLL cell trafficking, survival, proliferation, and the increase of the apoptotic threshold, which may be partly dependent on direct physical cell-to-cell contact or mediated through soluble factors. This crosstalk between CLL and the microenvironment is bidirectional; thus, CLL cells are not only being supported by the microenvironment but also are capable of activating and signaling through the secretion of mediators that sustain and promote their survival advantage. In vitro models and gene expression profiles have identified important pathways for the...

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Section: Immunoblottingmentioning

confidence: 99%

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Yeh¹,

Özer²,

Lehman³

et al. 2015

Blood

Self Cite

139

152

View full text Add to dashboard Cite

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“…16 Preclinical studies indicate that selective CDK9 inhibitors may have therapeutic potential for the treatment of various cancers and other human diseases. 17, 18 CDK9 regulates the levels of among others the prosurvival protein Mcl-1. Inhibition of CDK9 leads to reduced phosphorylation of Ser2 on RPB1, which results in the reduction of Mcl-1 levels.…”

mentioning

confidence: 99%

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

Robb¹,

Contreras²,

Kour³

et al. 2017

Chem. Commun.

185

141

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Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members. This is the first example of a PROTAC that selectively degrades CDK9.

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“…48,49 In addition, the gene encoding Mcl-1 is amplified in a variety of solid tumors. 50 In the case of ovarian cancer, tumors with Mcl-1 amplification have been found to be particularly resistant to conventional platinum-based chemotherapy.…”

mentioning

confidence: 99%

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

et al. 2015

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MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

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Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia

Cited by 40 publications

References 55 publications

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

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