Abstract
Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. We reported here DYRK1A expression level was reduced in the bone marrow of adult AML patients, comparing to normal controls. Overexpression of DYRK1A inhibited the proliferation of AML cell lines by increasing the proportion of cells undergoing G0/G1 phase. We reasoned that the proliferative inhibition was due to downregulation of c-Myc by DYRK1A, through mediating its degradation. Moreover, overexpression of c-Myc markedly reversed AML cell growth inhibition induced by DYRK1A. DYRK1A also had significantly lower expression in relapsed/refractory AML patients, comparing to newly-diagnosed AML patients, which indicated the role of DYRK1A in chemoresistance of AML. Our study provided functional evidences for DYRK1A as a potential tumor suppressor in AML.
Highlights
Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults
Primary antibodies for DYRK1A, cyclin D1, p21Waf1/Cip1 were purchased from CST (Beverly, MA), those for flag and b-actin were from Sigma-Aldrich (St Louis, MO), those for c-Myc was from Santa Cruz (Santa Cruz, CA), those for c-Myc pThr58 and pSer62 were from Immunoway (Newark, DE)
To further identified the genes that were responsible for the cell cycle arrest after DYRK1A overexpression, representative cell cycle regulators were studied. p21 was increased, while cyclin D1 and CDK2 were down-regulated by DYRK1A overexpression in AML cells (Figure 2E and F)
Summary
Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. The pathogenesis of AML involves variety of molecular abnormalities, mainly including activation of oncogenes and dysfunction of tumor suppressor genes [3]. We recently reported that dysregulation of DYRK1A reduced RE1 silencing factor (REST) protein stability and transcriptional activity through ubiquitination and subsequent degradation of REST protein [17]. This strongly suggests that the DYRK1A has anti-tumor effects in adult
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