Reconstructing the human hematopoietic niche in immunodeficient mice: opportunities for studying primary multiple myeloma.
Interactions within the hematopoietic niche in the BM microenvironment are essential for maintenance of the stem cell pool. In addition, this niche is thought to serve as a sanctuary site for malignant progenitors during chemotherapy. Therapy resistance induced by interactions with the BM microenvironment is a major drawback in the treatment of hematologic malignancies and bone-metastasizing solid tumors. To date, studying these interactions was hampered by the lack of adequate in vivo models that simulate the human situation. In the present study, we describe a unique human-mouse hybrid model that allows engraftment and outgrowth of normal and malignant hematopoietic progenitors by implementing a technology for generating a human bone environment. Using luciferase gene marking of patient-derived multiple myeloma cells and bioluminescent imaging, we were able to follow pMM cells outgrowth and to visualize the effect of treatment. Therapeutic interventions in this model resulted in equivalent drug responses as observed in the corresponding patients. This novel human-mouse hybrid model creates unprecedented opportunities to investigate species-specific microenvironmental influences on normal and malignant hematopoietic development, and to develop and personalize cancer treatment strategies.
Departments of Cell Biology.
Richard W J
RW
Groen
Willy A
WA
Noort
Reinier A
RA
Raymakers
Henk-Jan
HJ
Prins
Linda
L
Aalders
Frans M
FM
Hofhuis
Petra
P
Moerer
Jeroen F
JF
van Velzen
Andries C
AC
Bloem
Berris
B
van Kessel
Henk
H
Rozemuller
Ellen
E
van Binsbergen
Arjan
A
Buijs
Huipin
H
Yuan
Joost D
JD
de Bruijn
Michel
M
de Weers
Paul W H I
PW
Parren
Jan Jacob
JJ
Schuringa
Henk M
HM
Lokhorst
Tuna
T
Mutis
Anton C M
AC
Martens
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004429:Ear Ossicles / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D009368:Neoplasm Transplantation; D010014:Osteolysis / Q000276:immunology; D055153:Stem Cell Niche / Q000276:immunology*; D054457:Tissue Scaffolds; D018183:Transplantation Chimera / Q000276:immunology*; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000276:immunology*
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse