B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.

MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells

“…These observations are in line with data showing an anti-apoptotic effect of miR-125b, especially in the absence of growth factors or low-serum conditions, in several in vitro systems. 24,26,37,38 However, in contrast to others, we find only a limited impact of miR-125b on pre-B-cell proliferation, suggesting that this oncomiR has the dual potential to affect proliferative as well as apoptotic signaling pathways, depending on the priming events or cellular context. 26 The noted discrepancy, however, may be reconciled by the fact that in contrast to primary wild-type B-cell precursors, 1676 cells proliferate already at a high rate that can simply not be enhanced further by miR-125b.…”

“…Consistent with the need of a 'primed' genetic background, or 'second hits', to elicit its full transforming potential, we repeatedly failed to transform primary bone marrow-derived pre-B cells by miR-125b overexpression alone, recapitulating previous findings. 26 Accordingly, mice with a transgenic overexpression of miR-125b in early B cells develop leukemia only after long latency, indicating the requirement for additional pro-tumorigenic events. 12,23 Nevertheless, despite the need for immortalization, our data convincingly demonstrate that miR-125b is not only required for the process itself, but is also indispensable for the maintenance of the transformation (Figure 1).…”

“…[30][31][32] A manual analysis of this putative targets for an association with cancer as well as for signaling proteins, transcription factors and regulators of proliferation and survival narrowed the list down to 23 genes, most of which had not been investigated yet in the context of miR-125b overexpression, but also containing previously reported targets such as Arid3a, Abtb1 and Trp53inp1, validating our screening approach (Supplementary Table 5). 12,24,26 To test whether miR-125b indeed represses these genes, we co-expressed corresponding 3′-UTR reporter constructs with vectors encoding miR-125b, miR-125b mut or an empty control in 1676 pre-B cells. Flow cytometric analysis revealed that out of the 23 constructs, 12 showed little or no suppression when expressed with miR-125b, despite harboring conserved binding sites (Supplementary Figure S4).…”

“…9,12,17,[22][23][24][25][26] However, the precise molecular mechanism underlying the transforming activity of miR-125b remains unclear.…”

The microRNA-212/132 cluster regulates B cell development by targeting Sox4

“…In addition, miR-181 and miR-155 play an important role in B cell immune function by targeting AID to regulate classswitching and somatic hypermutation de Yébenes et al, 2008;Teng et al, 2008). Importantly, deregulation of the expression of many microRNAs important in B cell development and function results in autoimmunity (Xiao et al, 2008) and the onset of B cell cancers (Eis et al, 2005;Costinean et al, 2006;Calin et al, 2008;Xiao et al, 2008;Puissegur et al, 2012).…”