Development and progression of human leukemia using cellular and molecular biology

1. The identification of genes involved in chromosomal translocations

In T cell leukemias/lymphomas the a and d chains of the T cell antigen receptor are frequently involved in chromosomal translocations. We have isolated breakpoints on chromosome 11p13 and 10q24 and are currently studying the genes from chromosome 11 and 10 involved in these translocations. As well we have identified other translocations involving this region and are isolating those breakpoints.

2. The growth and regulation of acute myeloblastic leukemia (AML) cells

In culture and likely in vivo the growth of leukemic cells is regulated by agents that interact with cell surface receptors or hormone receptors. The Kit protein which is expressed on early hematopoietic progenitor cells is the receptor for a membrane-bound growth factor expressed by bone marrow stromal cells. We have found that Kit is expressed by the leukemic cells of most patients with AML. We are currently investigating the role of this protein in the growth of human leukemic cells.

Hormones such as retinoic acid can induce differentiation and inhibit the growth of AML cells. The effect of these agents is mediated by specific receptors that act within the nucleus of the cell to alter transcription. We are currently trying to identify those genes that are positively or negatively regulated by retinoic acid and determine whether those genes are important for the continued proliferation of AML cells.

Through an increased understanding of the genes involved in the growth of leukemic cells and the agents that can affect their expression we hope to be able to develop strategies that will permit us to regulate the leukemic cell in vivo.
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Khoury H, He R, Schimmer A, Beadle JR, Hostetler KY, Minden MD
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Luciani GM, Xie L, Dilworth D, Tierens A, Moskovitz Y, Murison A, Szewczyk MM, Mitchell A, Lupien M, Shlush L, Dick JE, Arrowsmith CH, Barsyte-Lovejoy D, Minden MD
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Professor, Department of Medical Biophysics, University of Toronto