CRIF1 Interacting with CDK2 Regulates Bone Marrow Microenvironment-Induced G0/G1 Arrest of Leukemia Cells

• Published in: PloS one Vol. 9; no. 2; p. e85328
• Main Authors: Ran, Qian, Hao, Ping, Xiao, Yanni, Xiang, Lixing, Ye, Xingde, Deng, Xiaojun, Zhao, Jiang, Li, Zhongjun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.02.2014; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Biology; Blood transfusions; Bone marrow; Bone Marrow - enzymology; Bone Marrow - metabolism; Bone Marrow - pathology; Case-Control Studies; Cell adhesion & migration; Cell culture; Cell cycle; Cell Cycle Proteins - metabolism; Cellular Microenvironment; Chemotherapy; Child; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinases; Cytokines; Cytoplasm; Depletion; Drug resistance; Enzyme inhibitors; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Leukemic; Gene therapy; Humans; Immunoprecipitation; Intracellular Space; Iron; Iron deficiency; Iron deficiency anemia; Jurkat Cells; Kinases; Laboratories; Leukemia; Leukemia - enzymology; Leukemia - pathology; Localization; Male; Medical research; Medicine; Middle Aged; mRNA; Myeloid leukemia; Nuclear Proteins - metabolism; Nuclei; Nuclei (cytology); Nutrient deficiency; Phosphorylation; Protein Binding; Protein Transport; Proteins; Remission; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; siRNA; Stem cells; Stromal cells; Studies; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0085328

To assess the level of CR6-interacting factor 1 (CRIF1), a cell cycle negative regulator, in patients with leukemia and investigate the role of CRIF1 in regulating leukemia cell cycle. We compared the CRIF1 level in bone marrow (BM) samples from healthy and acute myeloid leukemia (AML), iron deficiency anemia (IDA) and AML-complete remission (AML-CR) subjects. We also manipulated CRIF1 level in the Jurkat cells using lentivirus-mediated overexpression or siRNA-mediated depletion. Co-culture with the BM stromal cells (BMSCs) was used to induce leukemia cell cycle arrest and mimic the BM microenvironment. We found significant decreases of CRIF1 mRNA and protein in the AML group. CRIF1 overexpression increased the proportion of Jurkat cells arrested in G0/G1, while depletion of endogenous CRIF1 decreased cell cycle arrest. Depletion of CRIF1 reversed BMSCs induced cell cycle arrest in leukemia cells. Co-immunoprecipitation showed a specific binding of CDK2 to CRIF1 in Jurkat cells during cell cycle arrest. Co-localization of two proteins in both nucleus and cytoplasm was also observed with immunofluorescent staining. CRIF1 may play a regulatory role in the BM microenvironment-induced leukemia cell cycle arrest possibly through interacting with CDK2 and acting as a cyclin-dependent kinase inhibitor.