Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology.

Abstract

The distinct nature of acute lymphoblastic leukemia (ALL) in adults, evidenced by inferior treatment outcome and different genetic landscape, mandates specific studies of disease-initiating mechanisms. In this study, we used NOD/LtSz-scid IL2Rγ null(c) (NSG) mouse xenotransplantation approaches to elucidate leukemia-initiating cell (LIC) biology in primary adult precursor B (pre-B) ALL to optimize disease modeling. In contrast with xenografting studies of pediatric ALL, we found that modification of the NSG host environment using preconditioning total body irradiation (TBI) was indispensable for efficient engraftment of adult non-t(4;11) pre-B ALL, whereas t(4;11) pre-B ALL was successfully reconstituted without this adaptation. Furthermore, TBI-based xenotransplantation of non-t(4;11) pre-B ALL enabled detection of a high frequency of LICs (<1:6900) and permitted frank leukemic engraftment from a remission sample containing drug-resistant minimal residual disease. Investigation of TBI-sensitive stromal-derived factor-1/chemokine receptor type 4 signaling revealed greater functional dependence of non-t(4;11) pre-B ALL on this niche-based interaction, providing a possible basis for the differential engraftment behavior. Thus, our studies establish the optimal conditions for experimental modeling of human adult pre-B ALL and demonstrate the critical protumorogenic role of microenvironment-derived SDF-1 in regulating adult pre-B LIC activity that may present a therapeutic opportunity.

• Authors: Bella Patel, Aditi Dey, Anna Z Castleton, Claire Schwab, Edward Samuel, Janani Sivakumaran, Brendan Beaton, Nahid Zareian, Christie Yu Zhang, Lena Rai, Tariq Enver, Anthony V Moorman, Adele K Fielding
• Journal: Blood (Blood) Vol. 124 Issue 1 Pg. 96-105 (Jul 03 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24825861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Chemokine CXCL12
• Cxcl12 protein, mouse

Topics

• Adult
• Animals
• Cell Line, Tumor
• Chemokine CXCL12 (metabolism)
• Disease Models, Animal
• Flow Cytometry
• Graft Survival
• Heterografts
• Humans
• In Situ Hybridization, Fluorescence
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Neoplasm Transplantation (methods)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism, pathology)
• Tumor Microenvironment (physiology)