Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice

Abstract

The cellular components of the hematopoietic stem cell niche have been gradually identified. However, the niche for malignant hematopoiesis remains to be elucidated. Here, using human leukemia cells, which could be transplanted to immunodeficient mice, we studied the in vivo homing, proliferation and survival sites by immunohistopathology, compared with the corresponding sites for cord blood CD34 þ (CBCD34 þ ) cells. The human leukemia cells initially localized on the surface of osteoblasts in the epiphysial region, and expanded to the inner vascular and diaphysial regions within 4 weeks. The percentage of CD34 þ leukemia cells in the bone marrow was transiently increased up to 50%. In vivo 5-bromo-2 0 -deoxyuridine labeling revealed that the epiphysis was the most active site for leukemia cell proliferation. CBCD34 þ cells showed the similar pattern of homing and proliferation to leukemia cells. After high-dose administration of cytosine-1-b-D-arabinofuranoside, residual leukemia cells were localized in the perivascular endothelium as well as in contact with the trabecular endosteum. These findings suggest that xenotransplantation into immunodeficient mice provides a useful model to study the leukemia niche.

Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential

“…24 A leukemia niche has also been located in the trabecular endosteum. 25 In the present study, the leukemic niche could not be defined as most of the CD34 þ SSC lo ALDH br cells were interspersed in the intertrabecular area. Third, the overall NOD/ SCID engraftment levels in this study were lower than reported previously.…”

Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

“…[44][45][46] Leukemic stem cells are frequently drug resistant. [47][48][49] Our results point out that one of the first events involved in this process is decreased expression of the p53 tumor suppressor protein. Low levels of p53 are observed in acute myeloid leukemia (AML) blasts, whereas p53 mutations may not be so common.…”

How to Establish Acute Myeloid Leukemia Xenograft Models Using Immunodeficient Mice

“…These strains showed extremely high engraftment rates, resulting in remarkable advances in the development of AML mice models. These strains included the NOD/Shi-Prkdc scid Il2rγ tm1Sug /Jic (NOG) mice reported in 2002 (Ninomiya et al, 2006); and NOD/ LtSz-Prkdc scid Il2rγ tm1Wjl /J (NSG) mice reported in 2005 (Shultz et al, 2005). Compared to NS, the IL-2Rg-chain deficiency in NSG mice impaired the signaling through multiple cytokine receptors blocking NK development and resulted in additional defects in innate immunity (Shultz et al, 2005;Shultz et al, 2007).…”