Defining the significance of IGF2BP1 overexpression in t(12;21)(p13;q22)-positive leukemia REH cells

Abstract

The IGF2 mRNA binding protein 1 (IGF2BP1) belongs to a family of regulatory RNA-binding proteins and controls stability, transport or translation of its target transcripts. Re-expression of IGF2BP1 is frequently found in different tumors and has been associated with aggressive disease phenotypes. IGF2BP1 has also been identified to be exclusively specific for t(12;21)(p13;q22)-positive acute lymphoblastic leukemia (ALL) but biological significance of IGF2BP1 overexpression has not been investigated to date. We have recently reported that ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive ALL suggesting a direct role of IGF2BP1 in ETV6/RUNX1-mediated leukemogenesis. To address this question we have employed stable clones of REH cells - a model cell line of t(12;21)(p13;q22)-positive ALL - with downregulated IGF2BP1 expression. Here we show that downregulation of IGF2BP1 impairs proliferation by attenuating cell cycle progression and increasing the rate of spontaneous cell death. We also provide evidence that downregulation of IGF2BP1 induce reduction of STAT3 mRNA levels and augments sensitivity to STAT3 selective inhibitor S3I-201. These data imply that IGF2BP1 indirectly potentiates ETV6/RUNX1-RAC1-STAT3 signaling axis by sustaining appropriate ETV6/RUNX1 and STAT3 transcript levels in REH cells. Further studies are warranted to specify the role of IGF2BP1 in t(12;21)(p13;q22)-positive ALL.

Keywords: ETV6/RUNX1; IGF2BP1; S3I-201; STAT3; TEL-AML1; t(12;21)(p13;q22).