Evidence for a role of a lncRNA encoded from the p53 tumor suppressor gene in maintaining the undifferentiated state of human myeloid leukemias

Many human myeloid leukemias represent proliferating progenitor cells that are blocked in their ability to undergo terminal differentiation. The ability to induce differentiation of these cells has been used as a strategy of cancer therapy. During our analysis of the structure and regulation of expression of the p53 tumor suppressor gene we identified a gene encoding a long non-coding RNA (lncRNA) molecule within the 10,000 bp first intron. Here we demonstrate that this novel lncRNA is expressed in undifferentiated human myeloid leukemia cells and significantly reduced during the terminal differentiation of these cells into monocytes or macrophages. Thus, we hypothesize that this lncRNA may play some role in differentiation and be required to maintain the proliferative undifferentiated state. Recently, numerous long non-coding RNA molecules have been demonstrated to function as important regulators of gene expression and shown to be involved in numerous pathways, particularly pathways dealing with cellular differentiation. Since this lncRNA, which we have named lncRNAp53int1, appears to play some role terminal differentiation of human promyelocytes, our goal is to identify the function and mechanism of action of this novel transcript. We hypothesize that it may function in a non-coding fashion as part of an uncharacterized ribonucleoprotein complex or in some other fashion to participate in the maintenance of the undifferentiated state. Our findings show that it may participate in inhibiting the expression of the p21 gene, a known negative regulator of the cell cycle. That this lncRNA is reduced in its expression during terminal differentiation of human leukemic cells is particularly intriguing in that the ability to induce differentiation of leukemic cells has been used as a therapeutic strategy for over 30 years. Differentiation therapy continues to hold promise as new targets that control differentiation are defined. A regulatory role for lncRNAp53Int1 in leukemic cell differentiation would provide us with a new and potentially powerful target with respect to therapeutics.