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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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 7

Blocking the CD70-CD27 interaction inhibits LSC proliferation and prolongs survival.

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Blocking the CD70-CD27 interaction inhibits LSC proliferation and prolon...
WT CML mice were treated i.p. every other day with 300 μg FR70 or control IgG from rat serum starting at the day of transplantation. (A) Numbers of BCR/ABL-GFP+ granulocytes/μl in blood (n = 5 animals per group). (B) Kaplan-Meier survival curves. Pooled data from 2 independent experiments with FR70-treated (dotted line, n = 10) or IgG-treated (black line, n = 9) animals are shown. (C) Numbers of lin– BCR/ABL-GFP+ myelogenous progenitor cells and (D) LSCs per mouse 20 days after transplantation (n = 18 mice per group, pooled data from 2 independent experiments). (E and G) Immunostainings for (E) active β-catenin (spliced together from the same microscopic field of view) and (G) TNIK in LSCs from WT CML mice treated with IgG or FR70, 20 days after transplantation. Overlays of DAPI and β-catenin and DAPI and TNIK, respectively, are shown. Scale bars: 10 μm. (F and H) Percentages of LSCs positive for (F) nuclear active β-catenin and (H) nuclear TNIK. 175–216 cells were analyzed per group. (I) Cell cycle analysis by DAPI staining of LSCs from IgG-treated and FR70-treated WT CML mice. (J) 20 days after primary transplantation, 3 × 106 BM cells from IgG-treated or FR70-treated WT CML mice were pooled and secondarily transplanted into irradiated (4.5 Gy) BL/6 mice. Kaplan-Meier survival curves resulting from secondary transplantations are shown. Data are displayed as mean ± SEM. Statistics: 2-way ANOVA (A), log-rank test (B and J), Student’s t test (C, D, F, H, and I). Cells/mouse = cells from both femora, tibiae, and humeri.