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HOXB3 mRNA levels are high in the earliest CD34+ lineage- bone marrow cells and low to undetectable in later CD34+/CD34- cells. To gain some insight into the role this gene may play in hematopoiesis, HOXB3 was overexpressed in murine bone marrow cells using retroviral gene transfer. Thymi of HOXB3 marrow recipients were reduced in size compared with control transplant recipients, with a 24-fold decrease in the absolute number of CD4+ CD8+ cells and a 3-fold increase in the number of CD4- CD8- thymocytes that contained a high proportion of gammadelta TCR+ cells. B cell differentiation was also perturbed in these mice, as indicated by the virtual absence of transduced IL-7-responsive pre-B clonogenic progenitors. Recipients of HOXB3-transduced cells also had elevated numbers of mature granulocyte macrophage colony-forming cells in their bone marrow and spleen. Together these results suggest roles for HOXB3 in proliferation and differentiation processes of both early myeloid and lymphoid developmental pathways.

The miR-17-92 cluster and its 6 encoded miRNAs are frequently amplified and aberrantly expressed in various malignancies. This study demonstrates that retroviral-mediated miR-17-92 overexpression promotes expansion of multipotent hematopoietic progenitors in mice. Cell lines derived from these miR-17-92-overexpressing mice are capable of myeloid and lymphoid lineage differentiation, and recapitulate the normal lymphoid phenotype when transplanted to nonobese diabetic/severe combined immunodeficiency mice. However, overexpression of individual miRNAs from this locus, miR-19a or miR-92a, results in B-cell hyperplasia and erythroleukemia, respectively. Coexpression of another member of this cluster miR-17, with miR-92a, abrogates miR92a-induced erythroleukemogenesis. Accordingly, we identified several novel miR-92a and miR-17 target genes regulating erythroid survival and proliferation, including p53. Expression of this critical target results in marked growth inhibition of miR-92a erythroleukemic cells. In both murine and human leukemias, p53 inactivation contributed to the selective overexpression of oncogenic miR-92a and miR19a, and down-regulation of tumorsuppressive miR-17. This miR-17-92 expression signature was also detected in p53 ؊ B-cell chronic lymphocytic leukemia patients displaying an aggressive clinical phenotype. These results revealed that imbalanced miR-17-92 expression, also mediated by p53, directly transforms the hematopoietic compartment. Thus examination of such miRNA expression signatures should aid in the diagnosis and treatment of cancers displaying miR-17-92 gene amplification. (Blood. 2012;119(19):4486-4498) IntroductionHematopoiesis is regulated by genes governing cellular proliferation, differentiation, and apoptosis. Recent studies demonstrated that microRNAs (miRNAs), an important class of small nonprotein-coding RNA molecules, play a critical role during hematopoiesis by post-transcriptionally regulating the expression of critical genes involved in these processes. 1,2 Many miRNAs are specifically expressed in hematopoietic cells and their expression is dynamically regulated during hematopoiesis and lineage commitment. 1,3 Therefore it is not surprising that aberrant miRNA expression has frequently been observed in a wide variety of human cancers [4][5][6] and has been implicated in the initiation and progression of both solid and hematopoietic tumors. 7,8 Although the oncogenic and tumor-suppressor functions of miRNAs are not completely understood, it is known that miRNAs regulate the expression of key genes governing malignant transformation. 9,10 Recent studies revealed that aberrant miRNA expression may directly contribute to tumorigenesis. Our group identified the miR-17-92 locus as a retroviral insertion site in a subset of erythroleukemias induced in p53 knockout mice. 11 The miR-17-92 cluster produces a single polycistronic primary transcript processed to yield 6 individual mature miRNAs; miR-17, miR-18, miR-19a, miR-19b, miR-20, and miR-92a. This cluster is located on huma...