title: MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL.
abstract: Acute lymphoblastic leukemia in infants (< 1 year-of-age) is characterized by a high incidence of MLL rearrangements. Recently, direct targets of the MLL fusion protein have been identified. However, functional validation of the identified targets remained unacknowledged. In this study, we identify CDK6 as a direct target of the MLL fusion protein and an important player in the proliferation advantage of MLL-rearranged leukemia. CDK6 mRNA was significantly higher expressed in MLL-rearranged infant ALL patients compared with MLL wild-type ALL patients (P < 0.001). Decrease of MLL-AF4 and MLL-ENL fusion mRNA expression by siRNAs resulted in downregulation of CDK6, affirming a direct relationship between the presence of the MLL fusion and CDK6 expression. Knockdown of CDK6 itself significantly inhibited proliferation in the MLL-AF4-positive cell line SEM, whereas knockdown of the highly homologous gene CDK4 had virtually no effect on the cell cycle. Furthermore, we show in vitro sensitivity of MLL-rearranged leukemia cell lines to the CDK4/6-inhibitor PD0332991, inducing a remarkable G 1 arrest, and downregulation of its downstream targets pRB1 and EZH2. We therefore conclude that CDK6 is indeed a direct target of MLL fusion proteins, playing an important role in the proliferation advantage of MLL-rearranged ALL cells.
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Marieke H
authors.initials: MH
authors.lastname: van der Linden
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Merel
authors.initials: M
authors.lastname: Willekes
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Eddy
authors.initials: E
authors.lastname: van Roon
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Lidija
authors.initials: L
authors.lastname: Seslija
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Pauline
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology/Hematology; Erasmus MC - Sophia Children's Hospital; Rotterdam, The Netherlands.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Stam
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002459:Cell Fusion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007223:Infant; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D055273:Salivary Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; C524744:PRB1 protein, human; D010879:Piperazines; D011725:Pyridines; D055273:Salivary Proline-Rich Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: CDK6; MLL rearrangement; acute lymphoblastic leukemia; infant
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