Mark Kamps

Affiliation: UCSD SOM

Professor of Pathology

Biography

Mark P. Kamps received his BS degree in Biology and Chemistry at Calvin College and his PhD in Biochemistry from the University of California, San Diego. During his post-doctoral research at the Massachusettes Institute of Technology he cloned the first example of a chimeric transcription factor in human leukemia. Dr. Kamps became a PEW Scholar in 1991, a Leukemia and Lymphoma Society Scholar in 1996, and recieved the Stolhman Scholar award from the Leukemia and Lymphoma Society of America in 2002.

Research Summary

My laboratory is interested in the molecular mechanisms by which oncogenes prevent differentiation of hemopoietic stem cells and therein cause progenitor leukemias. We are particularly interested in how coexpression of the HoxA9 and Meis1 homeodomain transcription factors cause acute myeloid leukemia (AML), and how human oncoproteins such as Nup98-Nsd1 activate transcription of the subordinate HoxA9 and Meis1 proto-oncogenes in AML. To evaluate the myeloid transforming ability of oncoproteins, we use a well-characterized mouse model in which mice are transfused with cultured marrow stem cells infected by retrovirus expressing oncoproteins such as HoxA9 and Meis1. These mice acquire AML within 5 months (below). What is the normal function of HoxA9 and Meis1, how do they individually contribute to AML, and how is their transcription activated by human AML oncoproteins such as Nup98-Nsd1?

Project 1: How does HoxA9 stimulate self-renewal? In normal myeloid stem cells, expression of HoxA9 and Meis1 is down-regulated during terminal differentiation to neutrophils and macrophages, and knocking out HoxA9 or Meis1 reduces the numbers of myeloid progenitors in marrow, suggesting that HoxA9 and Meis1 normally control a switch from the self-renewing stem cell to the terminally differentiated phagocyte. We found HoxA9 prevents the normal differentiation of myeloid stem cells to macrophages & neutrophils, producing immortalized factor-dependent progenitors (Panel A, below). We produced forms of HoxA9 whose activity can be turned “on” or “off” (HoxA9-ER). This switchable HoxA9 protein controls morphologic differentiation of immortalized progenitors in an estrogen-dependent manner (Panel C, below) and serves as a master regulator of differentiation genes, maintaining the expression of cell division/immaturity transcription factor genes, such as c-Myb and c-Myc, and preventing expression of differentiation genes, such as the anti-microbial peptide gene, Cathelin (Cnlp; Panel B, below). The open questions in this project are:

How does HoxA9 regulate terminal differentiation gene promoters, preventing their expression?

How does HoxA9 maintain activation of the c-Myc and c-Myb genes?

What domains in HoxA9 are essential for these transcriptional activities, and how do they work?

Can we produce a drug inhibitor of HoxA9 activity that will act as an AML therapeutic?

Project 2: How does Meis1 induce the leukemic stem cell phenotype? We discovered that when HoxA9-immortalized progenitors are injected into mice, surprisingly, they do NOT cause AML. However, if we coexpressed Meis1 with HoxA9, immortalized progenitors now caused rapid AML in recipient mice (Panel B, below) even though they looked similar by microscopy (Panel A, below). Thus, Meis1 induced a “leukemic stem cell” property in non-leukemic progenitors. Interestingly, Meis1 activated transcription of stem cell genes encoding proteins expressed on virtually all human AMLs, including the FLT3 tyrosine protein kinase, the CD34 antigen, and the Erg1 transcription factor (Panel C, below). The open questions in this project are:

How does Meis1 activate transcription of these downstream target genes?

What biochemical activities does Meis1 recruit to activate leukemic stem cell gene transcription?

Project 3: How does Nup98-Nsd1 activate transcription of HoxA9 and Meis1? Our third project focuses on Nup98-Nsd1, a fusion protein produced by a newly-identified chromosomal translocation in human AML (Panel A, below). Nup98-Nsd1 contains a transactivation domain from Nup98 fused to the methyltransferase (SET) and PHD domains of Nsd1. SET domain transcription factors methylate histones and therein exact epigenetic gene regulation. PHD domains bind methylated histones, but the binding specificity of those in Nsd1 are unknown. Nsd1 is required for normal development and for expression of some Hox genes (Panel C, below), and mutations in a single Nsd1 allele cause Soto's syndrome, a cerebral gigantism/mental retardation syndrome (Panel B, below). We discovered that Nup98-Nsd1 causes AML in mice, that it activates transcription of HoxA9, maintains expression of Meis1, and requires both its SET and PHD domains for leukemic function. Open questions for project 3 include:

What are the biochemical functions of Nsd1 domains required for AML?

What specific methylated histone residues do the PHD domains in Nsd1 bind?

Do Soto's mutations in the PHD domains abrogate functions required for leukemogenesis by Nup98-Nsd1?

What transcription factor on the HoxA9 promoter is targeted by Nup98-Nsd1?

Is Nsd1 required for normal hematopoiesis?

Does Nsd1 control HoxA9 gene expression in hematopoiesis?

References

References From PubMed (NCBI)