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

Lookup NU author(s): Claire Schwab, Professor Anthony Moorman

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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 IL2R gamma 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.


Publication metadata

Author(s): Patel B, Dey A, Castleton AZ, Schwab C, Samuel E, Sivakumaran J, Beaton B, Zareian N, Zhang CY, Rai L, Enver T, Moorman AV, Fielding AK

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2014

Volume: 124

Issue: 1

Pages: 96-105

Print publication date: 03/07/2014

Online publication date: 13/05/2014

Acceptance date: 08/04/2014

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2014-01-549352

DOI: 10.1182/blood-2014-01-549352


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