Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability.
Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.
Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
Liran I
LI
Shlush
Noa
N
Chapal-Ilani
Rivka
R
Adar
Neta
N
Pery
Yosef
Y
Maruvka
Adam
A
Spiro
Roni
R
Shouval
Jacob M
JM
Rowe
Maty
M
Tzukerman
Dani
D
Bercovich
Shai
S
Izraeli
Guido
G
Marcucci
Clara D
CD
Bloomfield
Tsila
T
Zuckerman
Karl
K
Skorecki
Ehud
E
Shapiro
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001706:Biopsy; D001752:Blast Crisis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D018740:Genetic Heterogeneity; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D053842:Microsatellite Instability; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D012008:Recurrence; D059016:Tumor Microenvironment / Q000235:genetics
D000970:Antineoplastic Agents