Abstract
We have described a severe combined immunodeficiency (SCID) mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the growth potential of leukemic blasts from 133 patients with acute leukemia, (67 acute lymphoblastic leukemia (ALL) and 66 acute myeloid leukemia (AML)) in the animals after subcutaneous inoculation without conditioning treatment. The blasts displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 leukemias, 45 (33.8%) displayed an aggressive growth pattern, 14 (10.5%) displayed an indolent growth pattern and 74 (55.6%) did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was nearly 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. In addition, we demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course.
Highlights
Acute leukemia originates from transformed normal hematopoietic progenitor cells
We have developed a severe combined immunodeficiency (SCID) mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells and cells from the myeloid blast crisis of chronic myelogenous leukemia [16,17]
In this report we demonstrate that the proliferation ability of human leukemias in a SCID mouse model is associated with prognosis in acute human leukemias
Summary
Acute leukemia originates from transformed normal hematopoietic progenitor cells. The leukemogenic transformation may require multiple steps at the molecular and cellular level. Most of the reports were based on studies of a short-term (3 or 7 days) culture of the leukemia blasts in serum-free medium by a 3H-thymidine incorporation assay or based on a 7 days colony forming assay in methylcellulose medium to predict the leukemia blast proliferation activity [2,4,9,10]. Under these conditions, a substantial portion of blasts die due to apoptotic pressure from the in vitro cell culture soon after the culture starts. These methods may at best represent the temporary in vitro growth ability of the blast cells, but they may not accurately reflect the individual, intrinsic, spontaneous proliferation and long-term proliferation potential of leukemic blasts
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