One in four patients with acute myeloid leukemia (AML), a major hematopoietic abnormality in the US, carry the 8;21 chromosomal translocation [t(8;21)]. This translocation disrupts the gene for a key hematopoietic Runx1/AML1 transcription factor and encodes the leukemic AML1-ETO protein. AML1-ETO modifies transcription program of myeloid cells by altering Runx1 subnuclear localization and deregulating Runx target genes. Not only does Runx1 control the expression of hematopoiesis-related genes, it may also transcriptionally regulate miRs, which have recently been implicated in human leukemias. However, this hypothesis has not been experimentally tested. Furthermore, role of miRs in myeloid cell biology and their deregulation in acute myeloid leukemias by chimeric proteins such as AML1-ETO remains under explored. Our central hypothesis is that miRs that are direct transcriptional targets of Runx1 in myeloid lineage are key regulators of hematopoiesis and leukemogenesis. This hypothesis will be tested by an integrated experimental approach. Through genome-wide miR profiling of AML patients carrying the t(8;21), we will identify and characterize miRs that are deregulated in leukemia (henceforth designated Deregulated in Leukemia-microRNAs or DiL-miRs;
Specific Aim 1. 1). By employing an integrated bioinformatics, cell biological and biochemical approach, we will focus on DiL-miRs that are direct transcriptional targets of either the wild type Runx1 or the leukemic AML1-ETO, potentially target key pathways or regulators in myeloid cells, and contribute to leukemogenic properties of AML1-ETO (Specific Aim 1.2). We anticipate that the study proposed in this Specific Aim will yield a focused subset of DiL-miRs with potential diagnostic value. The rationale for Specific Aim 2 is provided by the observation that the 3'UTR region of the translocated AML1- ETO gene transcript is contributed by the ETO gene and is distinct from that of the wild type Runx1 gene transcript. We will specifically focus on miRs that are predicted to target the 3'UTR of AML1-ETO but not that of Runx1 gene transcript. These miRs will be assessed for their potential to partially or fully reverse the leukemic properties of AML1-ETO in patient-derived leukemia cell lines. We anticipate that the outcome of this Specific Aim will yield a subset of miRs that specifically and selectively target AML1-ETO and are therapeutically relevant. We propose that understanding mechanisms through which DiL-miRs participate in myeloid cell biology as well as in pathology of AML will provide a novel dimension to developing specific and effective therapeutic approaches for treatment of leukemia.
This study will identify small non-coding RNA molecules (microRNAs (miRs)) that are direct transcriptional target of a key hematopoietic transcription factor, Runx1. Runx1 is a frequent target of chromosomal translocations in leukemias of myeloid lineage, a serious health concern in the US. Identification of miRs that are regulated by Runx1, and are deregulated when the Runx1 gene is disrupted by chromosomal translocations, have far-reaching mechanistic as well as therapeutic implications in hematopoiesis and leukemogenesis. !
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