Ikaros and Aiolos Inhibit Pre-B-Cell Proliferation by Directly Suppressing c-Myc Expression

Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B–cell differentiation

“…To identify Ikaros-regulated genes in pre-B cells genome wide and to probe the significance of increasing Ikzf1 and Ikzf3 expression during B-cell differentiation 12,13,17,18 (www.immgen.org; Figure 1B), we used retroviral gene transfer to express either wild-type Ikaros (HA-Ikaros-IRES-GFP) or the dominant negative Ikaros DNAbinding mutant 159A (HA-159A Ikaros-IRES-GFP) 13 (supplemental Figure 1A). We chose the mouse pre-B-cell line B3 as our experimental system, because B3 cells resemble proliferating pre-B (Fr.C') cells in their gene expression profile 13,30 (supplemental Figure 1B).…”

“…on May 11, 2018. by guest www.bloodjournal.org From regulate common target genes, [17][18][19] cooperate to silence the expression of the pre-BCR genes Igll1 and Vpreb1, and facilitate the transition from pre-BCR-driven proliferation to cell cycle arrest, differentiation, and Ig light chain rearrangement by directly or indirectly regulating the expression of Myc, cell cycle genes, and Rag1 and Rag2 13,17,[19][20][21][22] . Ikaros chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) data are available for human hematopoietic progenitors 23 and mouse thymocytes, 24,25 where Ikaros and Aiolos show highly similar binding.…”

“…Third, Ikaros is an inhibitor of cell cycle progression, 29 and previous analyses of Ikaros target genes in this pathway by retroviral gene transfer were only possible at time points when G1 arrest had already occurred. 18 To overcome these limitations, we have combined Ikaros ChIPseq with gene expression studies at enhanced temporal resolution. In addition to confirming several previously described Ikaros target genes, the global identification of Ikaros target genes allowed us to address questions that could not be approached by single gene studies.…”

Overexpression of Aiolos in Nalm-6 acute lymphoblastic leukaemia cells reduces apoptosis by suppressing phosphatase and tensin homologue deleted on chromosome 10 and activating the phosphatidylinositol-3-kinase/Akt signalling pathway

“…In addition, Aiolos directly binds to the c-Myc promoter and represses the expression of c-Myc in pre-B cells. Repression of c-Myc by Aiolos subsequently leads to the expression of p27 and the downregulation of cyclin D3 (17). P27 is a type of cyclin-dependent kinase inhibitor protein, which inhibits G1/S conversion and negatively regulates the cell cycle by inhibiting the functions of cell cycle regulators, including cyclin D3 (18,19).…”

From HSC to B-Lymphoid Cells in Normal and Malignant Hematopoiesis

“…Aiolos is not required during the early specification of the B and T lineages but is essential during further B cell maturation. They also act in concert to promote preB cell cycle exit and transition to small PreB stage (Ma et al, 2010).…”