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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 Article has an altmetric score of 5

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

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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 6

CD27 signaling increases the colony formation of LSCs in a Wnt/β-catenin–dependent manner.

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CD27 signaling increases the colony formation of LSCs in a Wnt/β-catenin...
(A) 103 FACS-purified LSCs from WT or Cd27–/– CML mice were directly plated in methylcellulose, and colonies were enumerated 7 days later. Pooled data from 2 independent experiments each run in triplicate are shown. Values of colonies are shown in relation to the mean of WT LSCs (=100%). (B) 5 × 103 FACS-purified GFP– HSCs (n = 7) or BCR/ABL-GFP+ LSCs (n = 8) from individual WT CML mice were incubated overnight with 5 × 104 irradiated (10 Gy) naive BL/6 or Cd70tg CD19+ B cells, followed by plating in methylcellulose. Colonies and total cells were enumerated after 7 days. Data illustrate the percentage change in colony or cell formation of naive BL/6 CD19+ versus CD70-Tg CD19+ coincubations in each individual WT CML sample (naive BL/6 CD19+ = 100%). Pooled results of 3 independently performed experiments are shown. (C–E) 5 × 103 FACS-purified LSCs from pooled WT CML mice were incubated overnight with or without 5 × 104 irradiated (10 Gy) naive BL/6 or Cd70tg CD19+ B cells in the presence or absence of (C and D) 60 μM indomethacin or (E) 100 ng/ml Wnt-3a or 1 μg/ml Sfrp-2, followed by plating in methylcellulose (± the respective compound). Numbers of colonies (C and E) and cells (D) per well were assessed 7 days later. Each condition was run in quadruplicate to sextuplicate. Data are displayed as mean ± SEM. Statistics: Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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