Comparison of Three Different NOD/SCID-Related Strains in Preclinical Models of Acute Leukemia.

Abstract

Transplantation of human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) primary cells and cell lines in a variety of different strains of immunodeficient mice has led to preclinical models extensively used to investigate AML and ALL stem cells, biology, and drug sensitivity. We investigated the engraftment kinetics of two AML cell lines (HL-60 and KG-1), two ALL cell lines (MOLT-16 and 697) and AML primary cells from an AML M4 patient (QD1-EIO, described in Fusetti et al, Cancer Res 2000) in 3 different strains of NOD/LtSz-Prkdcscid(NOD/SCID, NS)-related immunodeficient mice. NS, NS/beta2 null (NSB) and NOD/SCID/IL-2Rgamma null (NSG) mice were injected ip with 10x106 AML or ALL cells. Mice were observed daily and sacrificed when leukemia-related symptoms were evident. Overall, leukemia-related symptoms were observed in 71, 84 and 86% of NS, NSB and NSG mice, respectively (n=42, p<0.01), after a median of 53, 49 and 35 days (p<0.001). Leukemia engraftment was investigated in the marrow, the blood and the spleen by means of morphology, flow cytometry and quantitative PCR for human genes. AML HL-60 and KG-1 cells accounted for 10-6, 5-1 and 7-3 % of peripheral blood cells in NS, NSB and NSG mice, respectively. ALL MOLT-16 and 697 cells accounted for 2-12, 22-27 and 1-27 % of blood cells in NS, NSB and NSG mice, respectively. AML primary cells QD1-EIO accounted for <1, <1 and 3% of blood cells in NS, NSB and NSG mice, respectively. Similar engraftment results were observed in the marrow and in the spleen. Leukemia cell-injected NSG mice, compared to NS and NSB, showed a significantly higher increase of circulating endothelial mature cells (CEC, enumerated by flow cytometry as CD45−, CD13+ VEGFR2+ cells) and progenitors (CEP, enumerated by flow cytometry as CD45−, CD13+ VEGFR2+ CD117+ cells, see Shaked et al, Cancer Cell 2005). This CEC and CEP increase paralleled leukemia engraftment. Taken together, our data indicate that the 3 different strains have significantly different leukemia engraftment behavior and kinetics. Engraftment in NSG mice is significantly faster compared to the other two strains, leukemia-related microenvironment is differently modulated, and less leukemic burden might be needed to observe leukemia-related symptoms. These data might have major implications to design future studies on leukemia-initiating stem cells, leukemia biology and preclinical leukemia treatment studies.