CDK6 as a key regulator of hematopoietic and leukemic stem cell activation

Scheicher, Ruth; Hoelbl-Kovacic, Andrea; Bellutti, Florian; Tigan, Anca-Sarmiza; Prchal-Murphy, Michaela; Heller, Gerwin; Schneckenleithner, Christine; Salazar, María; Zöchbauer‐Müller, Sabine; Zuber, Johannes; Malumbres, Marcos; Kollmann, Karoline; Sexl, Veronika

doi:10.1182/blood-2014-06-584417

Cited by 195 publications

(197 citation statements)

References 52 publications

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“…Studies in mouse models have shown that the cdk4-cyclin D1 interaction is necessary for maintaining tumour cell proliferation; mice lacking cdk4 are resistant to cancers driven by certain oncogenes, such as her2 4 . However, although cdk4 and cdk6 have 71% amino acid homology, a recent publication has suggested a new role for cdk6 in activating hematopoietic stem cells 5 . Thus, it could be hypothesized that the myelosuppression seen in palbociclib could result from an inhibition of cdk6 and, hence, hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Does CDKN2A Loss Predict Palbociclib Benefit?

2015

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Palbociclib, an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6, was recently approved by the U.S. Food and Drug Administration in combination with letrozole for postmenopausal women with advanced hormone receptor-positive, her2-negative breast cancer. Patients with loss of CDKN2A (p16), an inherent negative regulator of cyclin-dependent kinases 4 and 6, were not separately studied because of the significant response of the patients selected based only on receptor status. Here, we report a patient with metastatic estrogen receptorpositive, her2-negative breast cancer with CDKN2A loss who experienced a clinical response to palbociclib.

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Section: Discussionmentioning

confidence: 99%

Does CDKN2A Loss Predict Palbociclib Benefit?

2015

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“…[29][30][31] The protumorigenic functions of CDK6, but not of CDK4, go well beyond driving the cell cycle: in lymphoid and myeloid leukemia, CDK6 is part of transcriptional complexes that promote leukemogenesis and tumor formation. 32,33 CDK6 also directly regulates the transcription of factors that link neoplastic progression to the reprogramming of stem cells. 33 We now report the results of a screen of compounds approved by the US Food and Drug Administration (FDA).…”

Section: Introductionmentioning

confidence: 99%

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

Uras

Walter

Scheicher

et al. 2016

Blood

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102

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Key Points• CDK6 directly regulates transcription of FLT3 and PIM1 in a kinase-dependent manner.• CDK6 kinase inhibition impairs not only FLT3-dependent cell growth in vitro but also FLT3-driven leukemogenesis in vivo.Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD 1 acute myeloid leukemia;however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors. (Blood. 2016; 127(23):2890-2902

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“…Interestingly, EGR1 is regulated by multiple factors in AML. The cyclin-dependent kinases (CDK) CDK6 and Src family kinases (SFKs) inhibit expression of EGR1 (81,82). On the contrary, Llgl1 (lethal giant larvae homolog 1) and PMA (Phorbol 12-myristate 13-acetate) contribute to the differentiation of hematopoietic stem cells (83,84).…”

Section: Pathogenesis Mechanism Of Aml By Egr1mentioning

confidence: 99%