Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia.
Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL.
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
D
D
Pal
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
H J
HJ
Blair
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
A
A
Elder
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
K
K
Dormon
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
K J
KJ
Rennie
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
D J L
DJ
Coleman
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.|Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
J
J
Weiland
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
K S
KS
Rankin
Flow Cytometry Core Facility, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
A
A
Filby
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
O
0000-0001-5404-6483
O
Heidenreich
Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.|Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
J
J
Vormoor
D000818:Animals; D002448:Cell Adhesion; D002999:Clone Cells / Q000473:pathology; D018920:Coculture Techniques / Q000379:methods*; D004359:Drug Therapy, Combination / Q000379:methods; D061252:Feeder Cells / Q000166:cytology; D064593:Heterografts; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*