Abstract

Introduction: Mantle cell lymphoma (MCL) has a poor outcome and is a therapeutic challenge. Preclinical evaluation of investigational agents for MCL has been limited by lack of suitable animal models that mimic the natural history of human MCL and provide the microenvironment in which MCL cells thrive. Since MCL usually involves the bone marrow, we developed an in vivo mouse model for primary human MCL cells in severe combined immunodeficient mice (SCID-hu), which have been implanted with human fetal bone.

Materials and Methods: Human primary MCL cells were obtained and isolated from spleen, lymph nodes, bone marrow aspirates, or peripheral blood of six different MCL patients. Purified patient primary MCL cells were directly inoculated into human fetal bone chip or injected into mouse tail vein. Immunohistochemical staining with anti-human CD20 or cyclin D1 antibodies and detection of circulating human beta 2-microglobulin (B2M) in mouse serum were used to monitor the engraftment, growth, and immigration of human primary MCL cells in SCID-hu mice.

Results: A total of 30 SCID-hu mice and 5 SCID mice were used. Twenty of SCID-hu mice received inoculation of 0.5 – 5 × 106 of patient primary MCL cells (2–5 SCID-hu mice/patient sample) into human fetal bone chips implanted in mice subcutaneously. Five of SCID-hu mice and 5 of SCID mice (without human fetal hone chips) were injected intravenously with 5 × 106 of patient MCL cells. The same number of cells were injected into human bone chips in 5 SCID-hu mice with equal volume of PBS as controls. Successful primary MCL cell engraftment was observed in 15 out of 20 SCID-hu mice after injection of these cells into human fetal bones. But only one out of 5 SCID-hu mice had successful engraftment after the intravenous injection of primary MCL cells into mouse tail vein. Importantly, none of SCID mice had successful engraftment after intravenous injection of 5 × 106 of primary MCL cells. These data indicated that human fetal bone provides a critical microenvironment for the survival and growth of primary MCL cells. Increasing levels of circulating human B2M in mouse serum were found after successful engraftment and growth of human primary MCL cells in SCID-hu mice. Immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies confirmed that, similar to the human disease, primary MCL cells homed to mouse lymph nodes, spleen, bone marrow, and gastrointestinal tract but not to mouse liver. Treatment of MCL-bearing SCID-hu mice with atiprimod suppressed B2M secreted by functioning human MCL cells and induced tumor regression.

Conclusion: Human primary MCL cells from patient were able to successfully engraft in SCID-hu mice, and mimiced the natural organ involvement of human disease homing to mouse lymph node, spleen, bone marrow, and gastrointestinal tract but not to liver. This in vivo model mimiced the natural biological features of human MCL and is therefore useful for preclinical evaluation of new therapeutic agents.

Author notes

Disclosure: No relevant conflicts of interest to declare.