NUCLEAR TRANSPORT IN THE GENESIS OF ACUTE LEUKEMIA

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DESCRIPTION (Applicant's Description): Nuclear transport is a rapidly advancing field of basic research that gained clinical importance with the recent discovery that can, an oncogene activated by chromosomal rearrangements in acute myelogenous leukemia, encodes a nuclear pore protein. Leukemias associated with can rearrangements tend to occur in young people and have a relatively poor prognosis. Several other nuclear transport proteins were subsequently linked to tumor production. These considerations lend urgency to understanding the role of CAN in leukemogenesis and pose the more general question of the role of abnormal nuclear transport in the causation of cancer. Two chromosomal rearrangements involving can have been described: fusion with the dek gene, associated with acute myelogenous leukemia, and fusion with the set gene, associated with acute undifferentiated leukemia. In spite of these associations and the fact that CAN mRNA is expressed preferentially in hematopoietic tissues, nuclear transport and the role of CAN have not been studied in hematopoietic cells. The applicants therefore propose to study the function of CAN and the role of its most common fusion form, DEK-CAN, in a myeloid cell line and in bone marrow cells from leukemic patients. The hypothesis is that rearrangements involving 'can' result in failure to import nuclear factors necessary for differentiation due to an abnormal rate of nuclear transport, leading to malignant transformation of myeloid cells. To test their hypothesis they will stably transfect HL60 cells (an acute myelogenous leukemia cell line) with a construct that expresses the DEK-CAN fusion protein and examine the ultrastructure of the NPCs, the subcellular l o c a lization of CAN, nuclear import (of standard substrate and of transcription factors associated with myeloid differentiation), and the ability of the cells to undergo myeloid differentiation in response to in vitro stimuli. The same parameters (except for transcription factors and in vitro differentiation) will be studied in bone marrow cells from leukemic patients, but instead of comparing transfectants, bone marrow cells from patients with acute myelogenous leukemias with and without translocations involving 'can' will be compared. The ultimate goal of this research is to determine how translocations involving 'can' lead to leukemia, and hence begin to understand the role of nuclear transport abnormalities in the causation of cancer.