JS5-5 - Hematopoietic Stem Cell is the Primary Oncogenic Target in Human Leukemias

Abstract

ABSTRACT Malignant neoplasms might originate from a small abnormal cell population with deregulated self-renewal capacity, impaired differentiation activity and/or reinforced cell survival. This ‘cancer stem cell’ hypothesis is well supported in the field of hematologic disorders such as acute leukemias, based on identification of a small malignant stem cell fraction that can reconstitute human diseases in xenograft mouse models. In hematological malignancies, for perpetual propagation of leukemic mutations, these mutational events should occur in a cell population that can self-renew, otherwise the short life of a committed cell would not sustain these oncogenic events. We have successfully tracked the step-wise acquisition of mutations such as FLT3-ITD and AML1-ETO in hematopoietic stem cells (HSCs), which eventually developed de novo acute myelogeneous leukemia (AML). In contrast, in lymphoid malignancies, HSCs are not likely to play such a role in accumulation of mutations, because the clonality of lymphoid malignancies is usually found after the stage of rearrangement of T-cell receptor or immunoglobulin genes. However, we recently found that even in chronic lymphocytic leukemia (CLL), a mature B cell malignancy, the initial event for leukemic transformation could be traced up to HSCs. We found that mice transplanted with the CD34 + CD38- HSC fraction from CLL patients displayed expansion of monoclonal or oligoclonal CD5+ B cells. In contrast, normal HSCs always developed polyclonal CD5- B cells, suggesting that the primary deficit has occurred at the HSC stage in CLL patients. These data strongly support the hypothesis that HSCs are the cells that accumulate genetic abnormality to enable fully malignant transformation.