Research / Clinical Summary

Mark Kamps, PhD Professor, Pathology Hematologic Malignancies Program Contact by Email

Our laboratory focuses on the mechanism by which three human oncogenes contribute to acute myeloid leukemia. The first oncogene, HoxA9, blocks differentiation of mouse myeloid progenitors in culture. We have developed conditional versions of HoxA9 that immortalize progenitors when active and permit synchronous differentiation of such progenitors to neutrophils or macrophages when inactivated. Our goal is to use this model system to delineate transcriptional mechanisms by which Hoxa9 prevents transcription of differentiation genes and enforces transcription of progenitors genes such as Sox4.

The second oncogene we study is Meis1, which imparts the leukemic stem cell phenotype to HoxA9-immortalized progenitors. Our focus is on how Meis1 activates transcription of early stem cell genes such as CD34 and Flt3.

The third oncogene we study is Nup98-Nsd1, a chromosomal translocation protein that tethers the histone acetyltransferase activity of Nup98 to the histone methyltransferase transcription factor Nsd1. Interestingly, Nup98-Nsd1 immortalizes mouse myeloid progenitors and maintains transcription of both HoxA9 and Meis1. Our goal is to understand how Nup98-Nsd1 recognizes its target genes, such HoxA9, and how normal Nsd1 cooperates with other factors to regulate transcription of HoxA9. In recent unpublished results, we characterized the histone H3 methyl lysine binding specificity of each of the 6 Nsd1 PHD domains, discovering that they bind specifically to all three methylated form of H3K4 and H3K9, but do not bind the unmodified site. This suggests they recognize genes actively transcribed or targeted for activation.

In the context of analyzing how these transcription factors control gene transcription, we have recently been side-tracked on resolving the problem that myeloid progenitors contain copious amounts of proteases that hydrolyzes transcription factors such as HoxA9 during preparation of nuclear extracts, making biochemical approaches to promoter characterization untenable.

After screening numerous protease inhibitors, we have found that a combination of specific inhibitors to Cathepsin G and Elastase combined with the broad-specificity inhibitor alpha 1 anti-trypsin is an effective combination that inhibits the large majority of proteases released following myeloid progenitor cell lysis, and we are now using these conditions in transcriptional applications requiring the preparation of myeloid cell extracts.