Stop the dicing in hematopoiesis: what have we learned?
MicroRNAs (miRNAs) belong to an abundant class of highly conserved small (22nt) non-coding RNAs. MiRNA profiling studies indicate that their expression is highly cell type-dependent. DICER1 is an essential RNase III endoribonuclease for miRNA processing. Hematopoietic cell type- and developmental stage-specific Dicer1 deletion models show that miRNAs are essential regulators of cellular survival, differentiation and function. For instance, miRNA deficiency in hematopoietic stem cells and progenitors of different origins results in decreased cell survival, dramatic developmental aberrations or dysfunctions in mice. We recently found that homozygous Dicer1 deletion in myeloid-committed progenitors results in an aberrant expression of stem cell genes and induces a regained self-renewal capacity. Moreover, Dicer1 deletion causes a block in macrophage development and myeloid dysplasia, a cellular condition that may be considered as a preleukemic state. However, Dicer1-null cells do not develop leukemia in mice, indicating that depletion of miRNAs is not enough for tumorigenesis. Surprisingly, we found that heterozygous Dicer1 deletion in myeloid-committed progenitors, but not Dicer1 knockout, collaborates with p53 deletion in leukemic progression and results in various types of leukemia. Our data indicate that Dicer1 is a haploinsufficient tumorsuppressor in hematopoietic neoplasms, which is consistent with the observed downregulation of miRNA expression in human leukemia samples. Here, we review the various hematopoietic specific Dicer1 deletion mouse models and the phenotypes observed within the different hematopoietic lineages and cell developmental stages. Finally, we discuss the role for DICER1 in mouse and human malignant hematopoiesis.
Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Mir Farshid
MF
Alemdehy
Stefan J
SJ
Erkeland
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases