Abstract
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-RARα 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.
Highlights
Acute myeloid leukemia (AML) constitutes a heterogeneous group of tumors in myeloid lineage cells characterized by the proliferation and accumulation of immature myeloblasts [1]
Similar to the unsorted cells, one million CD342 fraction cells were able to engraft in recipient mice (4 out of 4 mice) (Figures 5C and 5D). These findings revealed that CD342 induced Acute promyelocytic leukemia (APL) cells exhibit the ability to function as APL-leukemia-initiating cells (LIC) in vivo, the LIC function was not excluded in the CD34+ APL fraction
Our present study revealed that a humanized APL model was successfully established by transplantation of human CD34+ cord blood transduced with PML-RARA into immunodeficient mice
Summary
Acute myeloid leukemia (AML) constitutes a heterogeneous group of tumors in myeloid lineage cells characterized by the proliferation and accumulation of immature myeloblasts [1]. In vivo analyses using a xenograft model with immunodeficient mice have shown that a very immature subset of AML cells called leukemic stem cells (LSC), which are typically characterized as CD34+/ CD382 cells, as observed in normal hematopoietic stem cells (HSCs), have been shown to slowly undergo cell division to both yield progenitor cells and sustain the LSC population, resulting in the maintenance of the tumor [2,3,4,5,6]. Acute promyelocytic leukemia (APL) is a subset of AML defined by the formation of a chimeric gene, promyelocytic leukemiaretinoic acid receptor a (PML-RARA) [8]. It is characterized by the accumulation of abnormal promyelocytes with abundant large azurophilic granules, suggesting that APL cells undergo maturation arrest in the later steps of myeloid differentiation. Elucidating the pathogenesis of APL is important for improving the treatment of APL patients, and will provide clues to understand the development of other subtypes of AML
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