Dataset Information

CDK6 degradation is counteracted by p16INK4A and p18INK4C in AML

ABSTRACT: Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase dependent and kinase independent effects, have been suggested as alternative therapeutic option. We show that efficacy of the CDK6 specific protein degrader BSJ-03-123 varies among AML subtypes and depends on low expression of the INK4 proteins p16INK4A and p18INK4C. INK4 protein levels are significantly elevated in MLL-AF9+ compared to AML1-ETO+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16INK4A or p18INK4C are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive marker for CDK6 degradation – targeted therapies in AML.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Hematopoietic Progenitor Cell Differentiation

DISEASE(S): Acute Myeloid Leukemia

SUBMITTER: Frédéric FONTAINE

LAB HEAD: Karoline Kollmann

PROVIDER: PXD032216 | Pride | 2022-04-04

REPOSITORIES: Pride

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Publications

CDK6 Degradation Is Counteracted by p16<sup>INK4A</sup> and p18<sup>INK4C</sup> in AML.

Schmalzbauer Belinda S BS Thondanpallil Teresemary T Heller Gerwin G Schirripa Alessia A Sperl Clio-Melina CM Mayer Isabella M IM Knab Vanessa M VM Nebenfuehr Sofie S Zojer Markus M Mueller André C AC Fontaine Frédéric F Klampfl Thorsten T Sexl Veronika V Kollmann Karoline K

Cancers 20220318 6

Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase-dependent and kinase-independent effects, have been suggested as an alternative therapeutic option. We show that the efficacy of the CDK6-specific protein degrader ...[more]

PMID: 35326705

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Project description:Cdk4 and Cdk6 are two related kinases that bind D-type cyclins and regulate cell cycle progression. Due to their relevance in cancer, Cdk4/6 inhibitors are currently in advanced clinical trials in multiple tumor types. Cdk4/6 are inhibited by INK4 proteins that exert tumor suppressing functions. To test the significance of this inhibitory mechanism we have generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6R/R mice display altered development of the hematopoietic system without resulting in enhanced tumor susceptibility, either in the presence or absence of p53. The presence of the Cdk6 R31C allele results in defective potential of hematopoietic progenitors in adoptive transfer assays or after induced damage. These defects are rescued after complete insensitivity to INK4 inhibitors in Cdk4R/R; Cdk6R/R double mutant mice, and INK4-resistant mice display increased susceptibility to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, the presence of the Cdk6 R31C allele results in increased binding of p16INK4a to wild-type Cdk4, whereas the double mutant is fully insensitive to INK4 inhibitors resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in tumor development and suggest a role for Cdk6 in buffering INK4 protein levels thus contributing to the development of hematopoietic tumors. The presence of the Cdk4 R24C and Cdk6 R31C alleles results in relevant changes in the expression profiles of cancer cells including deregulation of apoptosis and other processes. p185BCR-ABL1 was used to transform wild-type or double knock-in Cdk4 R24C; Cdk6 R31C fetal livers. Cell lines were isolated as spontaneous immortal and transformed clones after transduction of fetal liver with a p185 BCR-ABL1-transgene. RNA was isolated from asynchronous cultures. Two-condition experiment, Cdk4R-Cdk6R cells versus wild-type cells. Biological replicates: 3 control replicates, 3 transfected replicates.

Dataset Information

CDK6 degradation is counteracted by p16INK4A and p18INK4C in AML

Publications

CDK6 Degradation Is Counteracted by p16<sup>INK4A</sup> and p18<sup>INK4C</sup> in AML.

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