Low DICER1 expression is associated with attenuated neutrophil differentiation and autophagy of NB4 APL cells

Abstract

Successful myeloid differentiation depends on the expression of a series of miRNAs. Thus, it is hardly surprising that miRNAs are globally repressed in AML, a disease mainly characterized by a block in cellular myeloid differentiation. Studies investigating the mechanisms for low miRNA expression in AML has mostly focused on altered transcriptional regulation or deletions, whereas defective miRNA processing has received less attention. In this study, we report that the expression of the key miRNA processing enzyme DICER1 is down-regulated in primary AML patient samples and healthy CD34(+) progenitor cells as compared with granulocytes. In line with these findings, Dicer1 expression was induced significantly in AML cell lines upon neutrophil differentiation. The knocking down of DICER1 in AML cells significantly attenuated neutrophil differentiation, which was paralleled by decreased expression of miRNAs involved in this process. Moreover, we found that inhibiting DICER1 attenuated the activation of autophagy, a cellular recycling process that is needed for proper neutrophil differentiation of AML cells. Our results clearly indicate that DICER1 plays a novel role in neutrophil differentiation as well as in myeloid autophagy of AML cells.

Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy

“…We followed the methods of Wampfler et al [ 68 ]. Briefly, NB4 cells were fixed in 2% paraformaldehyde in PBS and permeabilized in 0.1% Triton X in PBS or fixed and permeabilized in methanol (−20°C) after cytospin.…”

The effect of miRNA and autophagy on colorectal cancer

“…135 Autophagy has been found to degrade the enzymes Dicer and AGO2 during miRNA processing and maturation in several tumours. 23,102,[136][137][138] However, this phenomenon has not been reported in CRC.…”

MicroRNAs in neutrophils: potential next generation therapeutics for inflammatory ailments

“…As neutrophils differentiate, there is an upregulation of 10 out of 15 of the miR biogenesis pathway members, including Dicer1. This implies the importance of the miRs in maintaining cell fate, as these components were also highly downregulated in acute myeloid leukemia and acute promyelocytic leukemia cell lines . The function of total miR in neutrophils by a neutrophil‐specific Dicer depletion has not been determined, but can be inferred from a C/EBPA‐Cre driven Dicer1 deletion mouse line.…”

“…Indeed, Dicer depletion in macrophages increases their propensity to form terminally differentiated multinucleated giant cells upon Th2 cytokine stimulation, a hallmark of granulomatous disease, 67 displaying an over-activation phenotype.As neutrophils differentiate, there is an upregulation of 10 out of 15 of the miR biogenesis pathway members, including Dicer1. This implies the importance of the miRs in maintaining cell fate, as these components were also highly downregulated in acute myeloid leukemia and acute promyelocytic leukemia cell lines 68. The function of total miR in neutrophils by a neutrophil-specific Dicer depletion has not been determined, but can be inferred from a C/EBPA-Cre driven Dicer1 deletion mouse line.…”