Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology.
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.
University College London, London, United Kingdom; and.
Bella
B
Patel
University College London, London, United Kingdom; and.
Aditi
A
Dey
University College London, London, United Kingdom; and.
Anna Z
AZ
Castleton
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Claire
C
Schwab
University College London, London, United Kingdom; and.
Edward
E
Samuel
University College London, London, United Kingdom; and.
Janani
J
Sivakumaran
University College London, London, United Kingdom; and.
Brendan
B
Beaton
University College London, London, United Kingdom; and.
Nahid
N
Zareian
University College London, London, United Kingdom; and.
Christie Yu
CY
Zhang
University College London, London, United Kingdom; and.
Lena
L
Rai
University College London, London, United Kingdom; and.
Tariq
T
Enver
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Anthony V
AV
Moorman
University College London, London, United Kingdom; and.
Adele K
AK
Fielding
D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006085:Graft Survival; D064593:Heterografts; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment / Q000502:physiology*
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse