CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression
Christian Schürch, … , Alexandar Tzankov, Adrian F. Ochsenbein
Christian Schürch, … , Alexandar Tzankov, Adrian F. Ochsenbein
Published January 9, 2012
Citation Information: J Clin Invest. 2012;122(2):624-638. https://doi.org/10.1172/JCI45977.
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Research Article Hematology

CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression

Abstract

Chronic myelogenous leukemia (CML) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein. Clinically, CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis. A CML-specific immune response is thought to contribute to the control of disease. Whether the immune system can also promote disease progression is not known. In the present study, we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells (LSCs) and mediates effects of the immune system on CML. In a mouse model of CML, BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27. Binding of CD27 by its ligand, CD70, increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active β-catenin and TRAF2- and NCK-interacting kinase (TNIK). This resulted in increased proliferation and differentiation of LSCs. Blocking CD27 signaling in LSCs delayed disease progression and prolonged survival. Furthermore, CD27 was expressed on CML stem/progenitor cells in the bone marrow of CML patients, and CD27 signaling promoted growth of BCR/ABL+ human leukemia cells by activating the Wnt pathway. Since expression of CD70 is limited to activated lymphocytes and dendritic cells, our results reveal a mechanism by which adaptive immunity contributes to leukemia progression. In addition, targeting CD27 on LSCs may represent an attractive therapeutic approach to blocking the Wnt/β-catenin pathway in CML.

Authors

Christian Schürch, Carsten Riether, Matthias S. Matter, Alexandar Tzankov, Adrian F. Ochsenbein

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Figure 3

CD27 signaling enhances proliferation and cell cycle progression of LSCs in vivo.

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CD27 signaling enhances proliferation and cell cycle progression of LSCs...
(A and B) Analysis of (A) naive HSC and (B) LSC proliferation by BrdU incorporation. Empty GFP-transduced naive Cd27–/– HSCs were used as a control in B. (C and D) Cell cycle analysis by DAPI stainings of (C) LSCs and (D) naive HSCs. Cells of n = 3–8 animals per group were pooled in each experiment. Pooled data from 4 independent experiments are shown. (E) LSCs pooled from 6 WT CML mice were separated by FACS sorting based on surface expression of CD27 (lo or hi), and BrdU incorporation was analyzed by FACS. (F) 103 FACS-purified, CD27 lo- or hi-expressing WT LSCs were plated into methylcellulose, and colonies and cells per well were enumerated 7 days later. (G–J) 2 × 104 LSCs from WT or Cd27–/– CML animals were isolated by FACS 20 days after primary transplantation and secondarily transplanted into irradiated (4.5 Gy) BL/6 recipients. (G) Granulocyte counts/μl blood (n = 3 mice per group) and (H) Kaplan-Meier survival curves resulting from secondary transplantations of WT (black line, n = 5) or Cd27–/– (dotted line, n = 7) LSCs (pooled data from 2 independent experiments). (I) Lin– c-kithi BCR/ABL-GFP+ myelogenous progenitor cell numbers and LSC numbers per mouse in the BM of BL/6 recipients 4 days after secondary transplantation. (J) Cell cycle analysis by DAPI stainings of LSCs in secondary CML 20 days after transplantation. BrdU incorporation was calculated as the difference in the percentage of α–BrdU-PE+ minus isotype control–PE+ cells. Data are displayed as mean ± SEM. Statistics: Student’s t test (A–F, I, and J), 2-way ANOVA (G), and log-rank test (H). Cells/mouse = cells from both femora, tibiae, and humeri.