Modeling Cml By Human Cells

【Background and Objective】Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm (MPN) raised from the haematopoietic stem cell (HSC). The Philadelphia (Ph) chromosome could be found in more than 90% of the CML patients, which is generated by t(9;22)(q34;q11) reciprocal translocation resulting in BCR– ABL fusion gene. The fusion gene encodes a constitutively active tyrosine kinase, which provides the potential therapeutic target. The development of tyrosine kinase inhibitors (TKIs) in late 20th century was thought to be one of the most successful translation from "bench" to "bed" . However, given the therapy discontinues relapse is nearly inevitable, which suggests that the disease is yet incurable by TKIs. The CML stem cells are presumed to be the source of relapse. Thus, further study of pathophysiological mechanisms of CML is reactivated, focusing on the characteristics of the CML stem cell and the bone marrow niche. For this purpose reliable animal model of this disease is essential. In the current study, humanised CML animal models were developed by xenotransplanting human cells in immunocompromised mice (NOG).【Methods】Three approaches were developed to established CML models: 1. K562 cells were injected into marrow cavity of tibia of NOD/SCID mice; 2. Mononuclear cells (MNCs) from CML patients' bone marrow were transplanted into newborn NOG mice via temporal vein injection. 3. BCR-ABL fusion gene were introduced into HSCs of human cord blood by lentiviral vector , followed by transplantation into NOG mice or inoculum in MS-5 cell-supported culture system.【Results】In NOG mice with CML patients cells, leukemic cells were consistently detected in bone marrow (expressing human specific antigen CD45), and the spleen was involved by leukemic infiltration; The behaviour and function of BCR-ABL transduced cord blood HSCs is under observation; In the K562 -transplanted mice, only solid tumors were raised in the place of injection, whereas none leukemic cells were detected in bone marrow. 【Conclusion】Transplantation of leukemic cells of CML patients could consistently propagate leukemia in NOG mice, thus provides a proper model for further studies; Transplantation of BCR-ABL-transduced human cord blood cells might develop CML-like disease in NOG mice, which is under observation; Transplantation of K562 cells in NOD/SCID is not suitable to develop CML model.