Protracted dormancy of pre-leukemic stem cells.

A M Ford,J Okamura,Y Kaneko,H Kobayashi,T Suzuki,F W Van Delft,M B Mansur,C L Furness,M Greaves

doi:10.1038/leu.2015.132

Abstract

Cancer stem cells can escape therapeutic killing by adopting a quiescent or dormant state. The reversibility of this condition provides the potential for later recurrence or relapse, potentially many years later. We describe the genomics of a rare case of childhood BCR-ABL1-positive, B-cell precursor acute lymphoblastic leukemia that relapsed, with an acute myeloblastic leukemia immunophenotype, 22 years after the initial diagnosis, sustained remission and presumed cure. The primary and relapsed leukemias shared the identical BCR-ABL1 fusion genomic sequence and two identical immunoglobulin gene rearrangements, indicating that the relapse was a derivative of the founding clone. All other mutational changes (single-nucleotide variant and copy number alterations) were distinct in diagnostic or relapse samples. These data provide unambiguous evidence that leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent but potentially reactivatable for more than two decades.

Highlights

Recurrence or relapse of cancer many years[1,2,3] or occasionally decades[4] after an initial diagnosis has been frequently recorded
A plausible mechanism for persistent, covert cancer cells during and after treatment is provided by the observation that some cancer stem cells can adapt a reversible quiescent or dormant state in which they are relatively resistant to radiation and chemotherapy.[5,6,7,8]
The assumption is usually made that late recurring cancer is a derivative of the original clone at diagnosis, evidence for which is very limited, with the exception of some acute leukemias where physiological rearrangement of immunoglobulin genes (IGH/IGK) provide clone-specific markers.[9,10,11]

Summary

Introduction

Recurrence or relapse of cancer many years[1,2,3] or occasionally decades[4] after an initial diagnosis has been frequently recorded. These observations raise difficult issues related to presumptions of cure, risk assessment and monitoring of residual disease. A plausible mechanism for persistent, covert cancer cells during and after treatment is provided by the observation that some cancer stem cells can adapt a reversible quiescent or dormant state in which they are relatively resistant to radiation and chemotherapy.[5,6,7,8] the assumption is usually made that late recurring cancer is a derivative of the original clone at diagnosis, evidence for which is very limited, with the exception of some acute leukemias where physiological rearrangement of immunoglobulin genes (IGH/IGK) provide clone-specific markers.[9,10,11]

Methods

Results

Conclusion