A kinase-independent role for CDK8 in BCR-ABL1+ leukemia

Menzl, Ingeborg; Zhang, Tinghu; Berger-Becvar, Angelika; Grausenburger, Reinhard; Heller, Gerwin; Prchal-Murphy, Michaela; Edlinger, Leo; Knab, Vanessa M.; Uras, Iris Z.; Grundschober, Eva; Bauer, Karin; Roth, Mareike; Skucha, Anna; Liu, Yao; Hatcher, John M.; Liang, Yanke; Kwiatkowski, Nicholas; Fux, Daniela; Hoelbl-Kovacic, Andrea; Kubicek, Stefan; Melo, Junia V.; Valent, Peter; Weichhart, Thomas; Grebien, Florian; Zuber, Johannes; Gray, Nathanael S.; Sexl, Veronika

doi:10.1038/s41467-019-12656-x

Cited by 36 publications

(35 citation statements)

References 58 publications

(73 reference statements)

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“…Curiously, our molecular dynamics simulations indicate that driver mutations in Med12, as opposed to triggering T-loop destabilization, instead promote reconfiguration of the Cdk8 T-loop into a stable conformation incompatible with efficient substrate binding and/or phosphorylation. This could effectively disable Cdk8 kinase activity, and, thus, circumvent a critical barrier to cellular transformation, while also preserving its structural integrity and retention of a critical kinase-independent (scaffolding) function required for cell viability ( 56 , 57 ). Ongoing studies designed to elucidate the structure and function of CKM variants incorporating oncogenic Med12 mutant derivatives should clarify these and other pressing issues.…”

Section: Discussionmentioning

confidence: 99%

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module

Chao

Kim

et al. 2021

Sci. Adv.

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The Cdk8 kinase module (CKM) in Mediator, comprising Med13, Med12, CycC, and Cdk8, regulates RNA polymerase II transcription through kinase-dependent and -independent functions. Numerous pathogenic mutations causative for neurodevelopmental disorders and cancer congregate in CKM subunits. However, the structure of the intact CKM and the mechanism by which Cdk8 is non-canonically activated and functionally affected by oncogenic CKM alterations are poorly understood. Here, we report a cryo–electron microscopy structure of Saccharomyces cerevisiae CKM that redefines prior CKM structural models and explains the mechanism of Med12-dependent Cdk8 activation. Med12 interacts extensively with CycC and activates Cdk8 by stabilizing its activation (T-)loop through conserved Med12 residues recurrently mutated in human tumors. Unexpectedly, Med13 has a characteristic Argonaute-like bi-lobal architecture. These findings not only provide a structural basis for understanding CKM function and pathological dysfunction, but also further impute a previously unknown regulatory mechanism of Mediator in transcriptional modulation through its Med13 Argonaute-like features.

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Section: Discussionmentioning

confidence: 99%

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module

Chao

Kim

et al. 2021

Sci. Adv.

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“…Conversely, deleting Ccnc (cyclin C) stimulates hyperplasia in thyroid and acute lymphoblastic leukemia mouse models (18,22). Interestingly, there is evidence that the CKM regulates transcription in both a CDK8 kinase-dependent and kinaseindependent manner (23). These studies indicate that the CKM plays a complicated role in transcriptional control responding to diverse inputs.…”

Section: Introductionmentioning

confidence: 99%

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

Stieg

Cooper

Strich

2020

Journal of Biological Chemistry

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The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C and one each of paralogs Cdk8/Cdk19, Med12/Med12L and Med13/Med13L. Our previous RNA-seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide-induced genes under normal conditions, but is involved in activating other loci following stress. Here, we show that cyclin C directs this transcriptional re-programing through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C indicating that the CKM moves as a single unit. It has previously been shown that some cyclin C leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. We observed that CKM integrity appeared compromised at a subset of repressed promoters suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters suggesting a mechanism to generate gene- and stress-specific responses.

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“…The combination of dasatinib and c-JUN N-terminal kinase (JNK) inhibitor, i.e., JNK-IN-8, can significantly improve the survival of the BCR-ABL1-positive mice model [161]. The cyclindependent kinases 8 (CDK8) inhibitor, YKL-06-101, combined with the mTOR inhibitor can induce cell death of human BCR-ABL1 leukemic cells [162]. Besides, both CDK4/6 inhibitors and Bcl-2 inhibitor are two types of molecular inhibitors that have been tested in R/R BCP-ALL [13,163], such as CDK4/6 inhibitors palbociclib (NCT02310243, NCT03472573, NCT03515200, NCT03132454, and NCT03792256) and Bcl-2 inhibitor venetoclax (NCT03826992, NCT03319901, NCT03181126, NCT04029688, NCT03808610, and NCT03504644).…”

Section: New Therapeutic Targets and Agents In Bcp-allmentioning

confidence: 99%

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Dai

et al. 2021

Front. Med.

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

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A kinase-independent role for CDK8 in BCR-ABL1+ leukemia

Cited by 36 publications

References 58 publications

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module

The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

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