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Haematologica 2018 Volume 103(6):1008-1017
*Present address: Department of Woman and Child Health, University of Padova, Italy.
**Present address: University Medical Center Tübingen, Department of Pediatrics and Adolescent Medicine, Tübingen, Germany.
***Present address: University of Pittsburgh, Department of Neurology, Pittsburgh, PA, USA. #KMD and LHM contributed equally to this work.
Ferrata Storti Foundation
Acute Lymphoblastic Leukemia
Leukemia reconstitution in vivo is driven by cells in early cell cycle and low metabolic state
Luca Trentin,1* Manon Queudeville,1** Sarah Mirjam Eckhoff,1 Nabiul Hasan,1*** Vera Münch,1,2 Elena Boldrin,1,2 Felix Seyfried,1 Stefanie Enzenmüller,1 Klaus-Michael Debatin1# and Lüder Hinrich Meyer1#
1Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center and 2International Graduate School in Molecular Medicine, Ulm University, Germany
ABSTRACT
In contrast to well-established hierarchical concepts of tumor stem cells, leukemia-initiating cells in B-cell precursor acute lymphoblastic leukemia have not yet been phenotypically identified. Different sub- populations, as defined by surface markers, have shown equal abilities to reconstitute leukemia upon transplantation into immunodeficient mice. Using a non-obese diabetes/severe combined immunodeficiency human acute lymphoblastic leukemia mouse model and cell cycle analysis anno- tating cells to distinct cycle phases, we functionally characterized leukemia-initiating cells and found that cells in all stages of the cell cycle are able to reconstitute leukemia in vivo, with early cycling cells (G1blow population) exhibiting the highest leukemia-initiating potential. Interestingly, cells of the G2/M compartment, i.e. dividing cells, were less effective in leukemia reconstitution. Moreover, G1blow cells were more resistant to spontaneous or drug-induced cell death in vitro, were enriched for stem cell signatures and were less metabolically active, as determined by lower levels of reactive oxygen species, compared to G2/M stage cells. Our data provide new information on the biological properties of leukemia-initiating cells in B-cell precursor acute lymphoblastic leukemia and underline the concept of a stochastic model of leukemogenesis.
Introduction
According to a hierarchical stem cell model, continuous proliferation of progen- itor and mature blood cells is sustained by hematopoietic stem cells (HSC) charac- terized by their ability to differentiate into all hematopoietic blood lineages while retaining self-renewal potential.1 In leukemia, the presence of a leukemia-initiating cell (LIC) was proven by studies showing that only CD34+/CD38– cells were able to transfer acute myeloid leukemia when transplanted into non-obese diabetes/severe combined immunodeficiency (NOD/SCID) mice, suggesting a hierarchical stem cell model in acute myeloid leukemia.2,3 Recent work challenged this view and showed that CD34–, CD34+/CD38+ and CD123+ cells were also able to reconstitute acute myeloid leukemia.4-8
In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), several studies have addressed the identification of LIC, demonstrating that more or less immature cells expressing different surface markers were all able to reconstitute leukemia in immunodeficient mice, supporting a stochastic stem cell model.9-13 Thus, the capac- ity to propagate BCP-ALL clearly appeared not to be restricted to a phenotypically defined subpopulation, but may rather be defined at a functional level. Previously, we identified two distinct engraftment phenotypes, i.e. "Time To Leukemia short" (TTLshort) and "Time To Leukemia long" (TTLlong), reflecting early and late engraft-
Correspondence:
lueder-hinrich.meyer@uniklinik-ulm.de or klaus-michael.debatin@uniklinik-ulm.de;
Received: February 24, 2017. Accepted: March 1, 2018. Pre-published: March 8, 2018.
doi:10.3324/haematol.2017.167502
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/1008
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