MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL

Marieke H. Van Der Linden, Merel Willekes, Eddyvan Roon, Lidija Seslija, Pauline Schneider, Rob Pieters, Ronald W. Stam

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

50 Citaten (Scopus)

Samenvatting

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 G1 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.

Originele taal-2Engels
Pagina's (van-tot)834-844
Aantal pagina's11
TijdschriftCell Cycle
Volume13
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 1 mrt. 2014
Extern gepubliceerdJa

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