Stephen Nimer, MD

Our laboratory has been investigating the transcriptional regulatory defects that underlie the hematologic cancers for more than a decade. We have focused predominantly on acute myelogenous leukemia but recently we have initiated projects to understand the molecular basis for other myeloproliferative diseases, and for lymphoproliferative disorders as well. We will utilize this knowledge to develop and test new treatment strategies for these diseases.

The recurrent chromosomal translocations found in acute myeloid leukemia (AML) usually involve at least one transcription factor gene. These genetic abnormalities may affect the level of gene expression but more commonly generate fusion or chimeric proteins with altered functional properties. Chromosomal 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 is the transcription factor (TF) core-binding factor (CBF), a heterodimeric complex composed of AML1 (CBFa) and CBFb.

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). CBFa (AML1/RUNX1) binds DNA directly, whereas CBFb enhances binding of CBFa_(AML1) to DNA but does not bind DNA itself. The importance of AML1 in hematopoiesis is demonstrated by the phenotype of AML1 and CBFb knock out mice, which lack definitive hematopoiesis; thus the AML1/CBFb complex is required for the development of adult hematopoietic stem cells.

Multiple myeloma and non-Hodgkin's lymphoma cells display aberrantly high levels of expression of certain proteins, which can be targeted by either molecularly based or immunologically based therapies. We have used gene microarrays and tissue arrays to characterize the expression of several gene families, including the polycomb group proteins, in these diseases.