Cornelis Murre
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Our general interests are in the molecular mechanisms that control stem cell maturation, lymphocyte development and lymphoid malignancies. Additionally, we are interested in the transcriptional control of lymphocyte cell death, cell growth and aging.
It is now well understood that the development of mature lymphocytes from multipotent progenitors requires the coordinated activities of a number of transcriptional regulators. Among these are the E2A proteins, E12 and E47. E12 and E47 are basic-helix-loop-helix (bHLH) transcription factors encoded by the E2A gene that bind DNA either as homodimers or as heterodimers with other bHLH proteins. Our previous data has indicated that E2A-encoded proteins are involved in the differentiation of a number of distinct cell types, including B cells and developing thymocytes. We are currently extending these studies. Additionally, we are investigating whether tissue specific transcriptional bHLH proteins have the ability to activate muscle, pancreatic and neuronal specific gene expression in multipotent lymphoid progenitor cells using retroviral gene transfer.
Recent data also have demonstrated that E12 and E47 have the remarkable ability to promote immunoglobulin VJ recombination in a human embryonic kidney cell line. Since the extreme N-terminal domain of E2A has been shown to recruit the co-activator protein complex, SAGA, which contains histone acetylase activity, it is conceivable that the E2A proteins regulate recombination by promoting locus accessibility. How E2A proteins regulate recombination is currently under study.
E2A protein expression in thymocytes is also required to initiate T-cell differentiation. During thymoctye development the E-proteins and their antagonists, Id2 and Id3, regulate T-lineage specific gene expression and TCR rearrangement. We have used a combination of the genetic and biochemical strategies to demonstrate that E2A and Id proteins act to block thymocyte maturation in the absence of pre-TCR expression, and that pre-TCR signaling acts to promote development in part by inhibiting E2A activity. Other systems under study include the regulation of E-protein activity by TCR signaling, the regulation of allelic exclusion, the role of E-proteins and Id3 in positive and negative selection as well as thymocyte survival and aging.
There is now considerable data indicating
that a significant fraction of lymphoid malignancies are in
large part due to the mutation and/or repression of E2A activity.
In pre-B acute lymphoblastoid leukemia, the N-terminal domain
of E2A gene is fused to either the C-terminal portion of HLF,
a leucine zipper encoding protein, or Pbx, a homeodomain gene
product. This particular set of leukemias show suboptimal
responses to antimetabolite chemotherapy that is effective
for most B-lineage leukemias. Thus it is important to establish
novel strategies for the treatment of these particular diseases.
As a first approach to this question we have identified a
number of down-stream targets for E2A/Pbx-1. One of these
is a novel growth factor, named Wnt-16, which in turn through
an autocrine loop activates the Wint signaling pathway in
pre-B cells. We suggest that the constitutive activation of
Wnt-16 in pre-B cells is a key step that ultimately leads
to the development of the leukemia. Work is in progress to
determine whether antagonists of Wint, for example secreted
forms of Wint receptors, named FrzBs, have the ability to
inhibit the activity of Wint-16 and block cell growth. Additionally,
we have recently initiated a study to identify small molecules
that would specifically inhibit E2A/Pbx1 DNA binding. Once
we have obtained positive results they may lead to immediate
novel avenues for the treatment of this particular form of
pediatric leukemia. Recent work in our laboratory has indicated
that the inactivation of E2A is a key step towards the development
of T-ALL. Also under study are genetic strategies using mice
with mutations that block T-cell development at defined stages
into an E2A-deficient background and hence would suggest explanations
for the mechanisms underlying tumor suppression. The screening
for regulatory targets of E2A will be a focus of further study.
Romanow, W.R., Langerak, A.W., Goebel, P., Wolvers-Tettero, I.L.M., van Dongen, J.J.M., Feeney, A.J. and Murre, C. (2000). E2A and EBF Act in Synergy with the V(D)J Recombinase to Generate a Diverse Immunoglobulin Repertoire in Non-Lymphoid Cells. Molecular Cell, 5: 343-353.
Bain, G., Cravatt, C.B., Loomans, C., Alberola-Ila, J., Hedrick, S.M. and Murre, C. (2001). Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-Erk MAPK cascade. Nature Immunology 2: 165-171.
Kee, B., Rivera, R. and Murre, C. (2001). Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-b Nature Immunology 2: 242-248.
Sayegh, C.E., Quong, M.E., Agata, Y. and Murre, C. (2003). E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nature Immunology 4: 586-593.
Ikawa, T., Kawamotot, H., Wright, L.Y.T. and Murre, C. (2004). Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. Immunity 3: 349-360.
Sayegh, C., Jhunjhunwala, S., Riblet, R. and Murre, C. (2005). Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. Genes Devel. 19: 322-327.
Dr. Murre performed his graduate work at Harvard Medical School and his postdoctoral studies at the Whitehead Institute for Biomedical Research.
