title: CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia.
abstract: Alterations in cell cycle pathways and retinoic acid signaling are implicated in leukemogenesis. However, little is known about the roles of cyclin-dependent kinases (CDKs) in treatment response of leukemia. In this study, we observed that CDK1 expression was significantly higher in bone marrow from 42 patients with acute myeloid leukemia (AML) at recurrence than that at first diagnosis (p = 0.04). AML patients had higher level of nuclear CDK1 in their leukemic blasts tended to have poorer clinical outcome compared with those with lower levels. We showed that CDK1 function is required for all-trans retinoic acid (ATRA) to achieve the optimal effect in U-937 human leukemic cells. CDK1 modulates the levels of P27(kip) and AKT phosphorylation in response to ATRA treatment. Further, we show, for the first time, that RARγ in concert with ATRA regulates protein levels of CDK1 and its subcellular localization. The regulation of the subcellular content of CDK1 and RARγ by ATRA is an important process for achieving an effective response in treatment of leukemia. RARγ and CDK1 form a reciprocal regulatory circuit in the nucleus and influence the function and protein stability of each other and the level of P27(kip) protein. In addition, expression of wee1 kinase and Cdc25A/C phosphatases also coincide with CDK1 expression and its subcellular localization in response to ATRA treatment. Our study reveals a novel mechanism by which CDK1 and RARγ coordinate with ATRA to influence cell cycle progression and cellular differentiation.
authors.affiliation: Department of Laboratory Medicine, Division of Experimental Cancer Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hedblom
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Laursen
authors.forename: Regina
authors.initials: R
authors.lastname: Miftakhova
authors.forename: Martuza
authors.initials: M
authors.lastname: Sarwar
authors.forename: Lola
authors.initials: L
authors.lastname: Anagnostaki
authors.forename: Anders
authors.initials: A
authors.lastname: Bredberg
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Persson
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002458:Cell Fractionation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000097768:Retinoic Acid Receptor gamma
chemical_list: D016203:CDC2 Protein Kinase; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D051058:Oncogene Protein v-akt; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C436291:CDKN1B protein, human
keywords: AML; CDK1; cell cycle; differentiation; leukemia; retinoic acid receptor; therapy