Journal Article

Tracing the origins of relapse in acute myeloid leukaemia to stem cells

Trotman-Grant, Aaron, McPherson, John D., Ng, Stanley W. K., Jaciw-Zurakowsky, Ivana, Dick, John E., Medeiros, Jessie J. F., Hudson, Thomas J., Abelson, Sagi, McLeod, Jessica L., Mitchell, Amanda, Heisler, Lawrence, Doedens, Monica, Rao-Bhatia, Abilasha, Shlush, Liran I., Minden, Mark D., Wang, Jean C. Y., Bader, Gary, Voisin, Veronique, Xu, ChangJiang, Marke, Rene

2017

Overview

Identification of the cell types from which relapse arises in acute myeloid leukaemia, by following leukaemia propagation from patient-derived leukaemia samples. AML relapse can develop from stem cells Relapse is frequently seen in patients with acute myeloid leukemia (AML). John Dick and colleagues now uncover the cell types from which relapse arises by following leukaemia propagation from patient-derived leukaemia samples. Surprisingly, they found that relapse can arise from two distinct leukaemia cell populations, both of which display stemness features. The first group consisted of rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, and the second were larger subclones of immunophenotypically committed leukaemia cells. These findings may help to better monitor and target relapse AML. In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission 1 . Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs 2 . However, other lines of evidence have pointed to the pre-existence of drug-resistant cells 3 . For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy 3 , 4 , 5 , suggesting that resistant cells are generated by evolutionary processes before treatment 3 and are selected by therapy 6 , 7 , 8 . Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells 9 , 10 have been linked to relapse owing to their dormancy and self-renewal properties 11 , 12 , 13 , and leukaemia stem cell gene expression signatures are highly predictive of therapy failure 14 , 15 , experimental studies have been primarily correlative 7 and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/100 / 45 / 45/23 / 631/181/2474 / 631/67/69 / 631/67/71 / 692/699/1541/1990/283/1897 / Acute myelocytic leukemia / Acute myeloid leukemia / Animals / Cell Lineage / Cell self-renewal / Chemotherapy / Clone Cells - metabolism / Clone Cells - pathology / Correlation analysis / Development and progression / Diagnosis / Dormancy / Drug resistance / Failure / Female / Functional analysis / Gene expression / Genomes / Hematopoietic stem cells / Humanities and Social Sciences / Humans / Immunophenotyping / letter / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Mice / multidisciplinary / Mutation / Myeloid Progenitor Cells - metabolism / Myeloid Progenitor Cells - pathology / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Origins / Patient outcomes / Patients / Physiological aspects / Progenitor cells / Recurrence (Disease) / Remission / Science / Signatures / Stem cells / Subpopulations / Survival / Transcription / Xenografts / Xenotransplantation