Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Beauchamp, Elspeth M.; Abedin, Sameem; Radecki, Sara G.; Fischietti, Mariafausta; Arslan, Ahmet Dirim; Blyth, Gavin T.; Yang, Angela; Lantz, Connor; Nelson, Alissa; Goo, Young Ah; Akpan, Imo; Eklund, Elizabeth A.; Frankfurt, Olga; Fish, Eleanor N.; Thomas, Paul M.; Altman, Jessica K.; Platanias, Leonidas C.

doi:10.1182/blood-2018-08-870089

Cited by 28 publications

(35 citation statements)

References 62 publications

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“…As described below, the identification of TORC1 or TORC2 substrates that are predominantly nuclear, further supports the idea of active TOR pools within the nucleus. It should also be noted that the mTORC1 subunits mLst8 and Raptor recently were characterized to be part of a novel complex that lacks mTOR but instead contains the CDK9 kinase which is a critical regulator of Pol II transcription elongation [89]. This mTORC1-like (CTORC1) complex regulates the transcription of genes involved in leukemogenesis.…”

Section: Subcellular Localization Of Tor and Its Activitymentioning

confidence: 99%

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee

Weisman

2020

Genes

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The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic stability. TOR affects nuclear functions indirectly through its activity in the cytoplasm, but also directly through active nuclear TOR pools. The mechanisms by which TOR regulates its nuclear functions are less well-understood compared with its cytoplasmic activities. TOR is an important pharmacological target for several diseases, including cancer, metabolic and neurological disorders. Thus, studies of the nuclear functions of TOR are important for our understanding of basic biological processes, as well as for clinical implications.

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Section: Subcellular Localization Of Tor and Its Activitymentioning

confidence: 99%

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee

Weisman

2020

Genes

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“…Cyclin-dependent kinase 9 (CDK9) is a key regulator of transcriptional elongation, which is a promising therapeutic target in cancer, particularly for types of cancer driven by transcriptional dysregulation (13,14). However, the mechanism and clinical transformation of CDK9 in CRC have been rarely reported (15).…”

Section: Introductionmentioning

confidence: 99%

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

et al. 2019

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Programmed death 1 (PD-1)-targeted therapy has benefited patients with microsatellite instability-high metastatic colorectal cancer (mCRC). However, the efficacy of PD-1-targeted therapy is poor in patients with microsatellite-stable (MSS) mCRC. Therefore, it is imperative to explore additional co-inhibitory molecular signalling pathways to improve the efficacy of immunotherapy in MSS mCRC treatment. In the present study, the association between cyclin-dependent kinase 9 (CDK9) expression and the survival of patients with CRC was analysed using RNA sequencing data from 605 patients, including 121 cases of mortality, from human cancer datasets. Furthermore, 35 clinical MSS stage III–IV CRC specimens were collected to assess CDK9 protein expression by immunohistochemistry, and the frequency of tumor-infiltrating CD8+ T cells was assessed by flow cytometry. The human cancer datasets demonstrated that upregulation CDK9 significantly shortened the survival of patients with stage II–IV colon cancer. Additionally, CDK9 mRNA expression was positively correlated with the expression levels of genes associated with immune evasion in the tumor. Notably, CDK9 was expression was upregulated in stage IV CRC compared with para-cancerous tissues and early-stage tumors. Interestingly, CDK9 expression was negatively associated with the infiltration of CD8+ T cells at the tumor site. In addition, the expression levels of T-cell immunoglobulin mucin family member 3 and CD39, proteins associated with exhaustion, on tumor-infiltrating CD8+ T cells were significantly elevated in patients with abnormal CDK9 expression levels. The present study demonstrated that CDK9 expression was negatively associated with CD8+ T cell infiltration and positively associated with CD8+ T cell exhaustion in MSS mCRC. In conclusion, CDK9 may be utilized to evaluate the prognosis and the immune-type of the tumor microenvironment in patients with MSS mCRC.

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“…Patients with t(8;21) demonstrated overall hypomethylation as compared to other groups, with all of the top 50 probes (mapping to 44 unique genes) significantly hypo-methylated as compared to non t(8;21) cases ( Table 2 ). These genes included MCF2L , a guanine nucleotide exchange factor implicated in gemcitabine resistance that also impacts Rho/Rac signaling [ 35 ]; SLC9A1 , involved in maintaining alkaline pH and Warburg effect and associated with chemo-resistance in solid tumors; FAM120B located in close proximity to MLLT4 , a known fusion partner in leukemia; DZIP1 , zinc finger protein 1, an oncogene involved in wnt/B catenin and Hedgehog signaling; genes with potential tumor suppressive effects; PTPRF that acts via deactivating ERK1/2 signaling; LARP1 that interacts with oncogenic transcripts and regulates mTOR post-transcriptionally with impact on CDK9 and mTOR interaction in leukemia [ 36 ]. A few selected examples from the t(8:21) specific paired methylation and expression signatures, are shown in Figure 3 panels A and B ( Table S3 shows the detailed results).…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML

Lamba

Cao

Raimondi

et al. 2020

Cancers

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Acute Myeloid Leukemia (AML) is characterized by recurrent genetic and cytogenetic lesions that are utilized for risk stratification and for making treatment decisions. In recent years, methylation dysregulation has been extensively studied and associated with risk groups and prognosis in adult AML, however, such studies in pediatric AML are limited. Moreover, the mutations in epigenetic genes such as DNMT3A, IDH1 or IDH2 are almost absent or rare in pediatric patients as compared to their abundance in adult AML. In the current study, we evaluated methylation patterns that occur with or independent of the well-defined cytogenetic features in pediatric AML patients enrolled on multi-site AML02 clinical trial (NCT00136084). Our results demonstrate that unlike adult AML, cytosine DNA methylation does not result in significant unique clusters in pediatric AML, however, DNA methylation signatures correlated significantly with the most common and recurrent cytogenetic features. Paired evaluation of DNA methylation and expression identified genes and pathways of biological relevance that hold promise for novel therapeutic strategies. Our results further demonstrate that epigenetic signatures occur complimentary to the well-established chromosomal/mutational landscape, implying that dysregulation of oncogenes or tumor suppressors might be leveraging both genetic and epigenetic mechanisms to impact biological pathways critical for leukemogenesis.

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Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Cited by 28 publications

References 62 publications

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML

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