Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability

• Published in: Blood 2012-07, Vol.120 (3), p.603-612
• Main Authors: Shlush, Liran I., Chapal-Ilani, Noa, Adar, Rivka, Pery, Neta, Maruvka, Yosef, Spiro, Adam, Shouval, Roni, Rowe, Jacob M., Tzukerman, Maty, Bercovich, Dani, Izraeli, Shai, Marcucci, Guido, Bloomfield, Clara D., Zuckerman, Tsila, Skorecki, Karl, Shapiro, Ehud
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biopsy; Blast Crisis - drug therapy; Blast Crisis - genetics; Blast Crisis - pathology; Cell Division - drug effects; Cell Division - genetics; Cell Lineage - genetics; Drug Resistance, Neoplasm - genetics; Flow Cytometry; Genetic Heterogeneity; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Microsatellite Instability; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Recurrence; Tumor Microenvironment - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-10-388629

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.