Stephen Nimer, MD

Our laboratory has been investigating the transcriptional regulatory defects that underlie the hematologic cancers for the past two decades. We have focused predominantly on acute myelogenous leukemia but recently we have initiated projects to understand the molecular basis for the myelodysplastic and myeloproliferative diseases, and for multiple myeloma as well. We will utilize this knowledge to develop and test new treatment strategies for these diseases.

Myeloid Disorders

The recurrent chromosomal translocations found in acute myeloid leukemia (AML) usually involve at least one transcription factor gene. These translocations (e.g., t(8;21)) or deletions (e.g., 20q-) often disrupt genes that are required for the normal development of blood cells; an example of which are the core-binding factor (CBF) genes, AML1 (CBFα) and CBFβ. Both components of CBF are affected by translocations found in human leukemias, including the t(8;21), t(3;21), t(12;21), and inv(16). CBFα (AML1/RUNX1) binds DNA directly, whereas CBFβ enhances binding of CBFα_(AML1) to DNA but does not bind DNA itself.

Our lab was the first to identify that the AML1-ETO protein functions as a transcriptional repressor and we next showed several gains of function that are not present in AML1. Using human CD34+ cells isolated from umbilical cord blood or mobilized peripheral blood progenitor cells, we demonstrated the ability of AML1-ETO to promote the cell renewal of human stem/progenitor cells. We also demonstrated that AML1-ETO delays but does not completely block differentiation. We have identified a variety of AML1-ETO target genes, that are up or down regulated in response to its expression. Ongoing work in the lab has been examining the mechanism by which AML1-ETO activates gene expression as gene activation appears to correlate with the ability to promote the self-renewal of hematopoietic stem/progenitor cells. It is our hope that in the near future we will be able to directly target this property of AML1-ETO.

We also have been evaluating how the AML1 protein regulates gene expression. To understand how to modulate the activity of AML1 versus AML1-ETO we have focused on the arginine methyltransferases (PRMTs) enzymes that add methyl groups to histone and non-histone proteins. We have shown that PRMT1 can work as a coactivator with AML1 to turn on genes, such as CD41 or PU.1. We have also identified other PRMTs that bind to and regulate AML1 activity. We hope to be able to use some of these enzymes as targets for novel therapies in leukemia.

In addition to studying oncogenes implicated in hematopoietic malignancies, we have been studying tumor suppressor genes such as the L3MBTL1 protein. This gene is located on 20q within the commonly deleted region for patients with hematological malignancies. We identified that L3MBTL1 functions as a repressor and that the MBT domains within L3MBTL1 form a novel three-bladed propeller-like structure. We have gone on to show that L3MBTL1 uses its second MBT domain to bind to mono- and dimethylated lysine residues in histone H1b and H4. More recent studies have implicated L3MBTL1 in the process of erythroid differentiation.

Lastly, we have been focusing on ways to alter the chemosensitivity and radiation sensitivity of tumor cells vs. normal cells, using mice engineered to lack the transcription factor MEF. Quiescent cells resist the effects of chemotherapy and radiation therapy and cells that lack MEF, show increased quiescence and decreased sensitivity to chemo or radiation therapy. We are studying the pathways involved in this process and thus far have implicated the p53 gene in controlling stem cell quiescence. We have also identified other target genes that are regulated by p53 and/or MEF that regulate quiescence and possibly, the response to chemotherapy. We will be examining these genes in both the leukemic stem cell and the normal stem cell, hoping to identify pathways that we can exploit to kill the malignant stem cell, but leave the normal stem cells intact.