TY - JOUR
T1 - Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding
AU - Belderbos, Mirjam E.
AU - Koster, Taco
AU - Ausema, Bertien
AU - Jacobs, Sabrina
AU - Sowdagar, Sharlaine
AU - Zwart, Erik
AU - de Bont, Eveline S J M
AU - de Haan, Gerald
AU - Bystrykh, Leonid V.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - Genetic and phenotypic heterogeneity of human leukemia is thought to drive leukemia progression through a Darwinian process of selection and evolution of increasingly malignant clones. However, the lackofmarkers thatuniquely identify individual leukemia clones precludes high-resolution tracing of their clonal dynamics. Here, we use cellular barcoding to analyze the clonal behavior of patient-derived leukemia-propagating cells (LPCs)inmurine xenografts. Using a leukemic cell line and diagnostic bone marrow cells from 6 patients with B-progenitor cell acutelymphoblastic leukemia, wedemonstrate that patient-derived xenografts were highly polyclonal, consisting of tenstohundreds of LPC clones. The number of clones was stable within xenografts but strongly reduced upon serial transplantation. In contrast to primary recipients, in which clonal composition was highly diverse, clonal composition in serial xenografts was highly similar between recipients of the same donor and reflected donor clonality, supporting a deterministic, clone-size-based model for clonal selection. Quantitative analysis of clonal abundance in several anatomic sites identified 2 types of anatomic asymmetry. First, clones were asymmetrically distributed between different bones. Second, clonal composition in the skeleton significantly differed from extramedul-lary sites, showing similar numbers but different clone sizes. Altogether, this study shows that cellular barcoding and xenotransplantation providea useful model to study the behavior of patient-derived LPC clones, which provides insights relevant for experimental studies on cancer stem cells and for clinical protocols for the diagnosis and treatment of leukemia.
AB - Genetic and phenotypic heterogeneity of human leukemia is thought to drive leukemia progression through a Darwinian process of selection and evolution of increasingly malignant clones. However, the lackofmarkers thatuniquely identify individual leukemia clones precludes high-resolution tracing of their clonal dynamics. Here, we use cellular barcoding to analyze the clonal behavior of patient-derived leukemia-propagating cells (LPCs)inmurine xenografts. Using a leukemic cell line and diagnostic bone marrow cells from 6 patients with B-progenitor cell acutelymphoblastic leukemia, wedemonstrate that patient-derived xenografts were highly polyclonal, consisting of tenstohundreds of LPC clones. The number of clones was stable within xenografts but strongly reduced upon serial transplantation. In contrast to primary recipients, in which clonal composition was highly diverse, clonal composition in serial xenografts was highly similar between recipients of the same donor and reflected donor clonality, supporting a deterministic, clone-size-based model for clonal selection. Quantitative analysis of clonal abundance in several anatomic sites identified 2 types of anatomic asymmetry. First, clones were asymmetrically distributed between different bones. Second, clonal composition in the skeleton significantly differed from extramedul-lary sites, showing similar numbers but different clone sizes. Altogether, this study shows that cellular barcoding and xenotransplantation providea useful model to study the behavior of patient-derived LPC clones, which provides insights relevant for experimental studies on cancer stem cells and for clinical protocols for the diagnosis and treatment of leukemia.
UR - http://www.scopus.com/inward/record.url?scp=85021068081&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-12-758250
DO - 10.1182/blood-2016-12-758250
M3 - Article
C2 - 28396495
AN - SCOPUS:85021068081
SN - 0006-4971
VL - 129
SP - 3210
EP - 3220
JO - Blood
JF - Blood
IS - 24
ER -