Recent advances in
cancer biology have revealed that many
malignancies possess a hierarchal system, and leukemic stem cells (LSC) or
leukemia-initiating cells (LIC) appear to be obligatory for
disease progression.
Acute promyelocytic leukemia (APL), a subtype of
acute myeloid leukemia characterized by the formation of a PML-RARĪ± fusion
protein, leads to the accumulation of abnormal promyelocytes. In order to understand the precise mechanisms involved in human APL leukemogenesis, we established a humanized in vivo APL model involving retroviral transduction of PML-RARA into CD34(+) hematopoietic cells from human cord blood and
transplantation of these cells into immunodeficient mice. The
leukemia well recapitulated human APL, consisting of leukemic cells with abundant azurophilic abnormal granules in the cytoplasm, which expressed CD13, CD33 and CD117, but not
HLA-DR and CD34, were clustered in the same category as human APL samples in the gene expression analysis, and demonstrated sensitivity to ATRA. As seen in human APL, the induced APL cells showed a low
transplantation efficiency in the secondary recipients, which was also exhibited in the
transplantations that were carried out using the sorted CD34- fraction. In order to analyze the mechanisms underlying APL initiation and development, fractionated human cord blood was transduced with PML-RARA. Common myeloid progenitors (
CMP) from CD34(+)/CD38(+) cells developed APL. These findings demonstrate that
CMP are a target fraction for PML-RARA in APL, whereas the resultant CD34(-) APL cells may share the ability to maintain the
tumor.