NOD/SCID/γ_c^null mice provide a Unique Model to Investigate Childhood Haematopoietic Malignancies

Remarkable improvements in the outcome for childhood haematopoietic malignancies have been made during the past few decades. However, haematopoietic malignancies are the most common pediatric malignancy, and outcome after relapse is generally poor. Recent reports suggest that at least some cases of human leukemia and cancer are arranged in a hierarchical fashion and maintained by rare “tumor-propagating cells”. However, whether the malignant clone arises from such a leukemic stem cell fraction has not been clarified in most haematopoietic malignancies other than acute myelogenous leukemia (AML). Establishment of an assay capable of generating of childhood haematopoietic malignancies from patient oriented blast cells will provide new insight into the haematopoietic malignancies biology and the mechanism of the development of haematopoietic malignancies in vivo. The recently described highly immunodeficient NOD/SCID/gamma null (NOG) mice provide a number of advantages. This strain, with life expectancy more than 90 weeks, is more robust than strains such as NOD/SCID and support generation of haematopoietic malignancies from transplanted human blast cells. In the present study, childhood haematopoietic malignancies cells, such as acute lymphoblastic leukemia(ALL; n=7), AML (n=4), juvenile myelomonocytic leukemia(JMML; n=1), Lymphoma(n=1), and Transient Myeloproliferative Disorder(n=1), are transplanted into 2.4Gy irradiated or non-irradiated NOG mice. The transplanted mice have splenomegaly, hepatomegaly, nephromegaly and testicular enlargement and developed haematopoietic malignancies which is the same flow cytometric immunophenotype and pathological pattern of the patient from 4 weeks after intravenous injection of 5×10²-1×10⁸ blast cells. The transplanted mice can live as long as 24 weeks after transplantation with more than 95% blasts in the bone marrow. The blast cells harvested from the bone marrow and the spleen generated the haematopoietic malignancies in tertiary transplantation especially in ALL. We report here examination results of reconstituted childhood haematopoietic malignancies in NOD/SCID/gamma null mice after the transplantation of patient oriented blast cells.