Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia

被引：60

作者：

Mangolini, Maurizio ^{[1
,2
]}

Goette, Frederik ^{[3
]}

Moore, Andrew ^{[1
,2
]}

Ammon, Tim ^{[3
]}

Oelsner, Madlen ^{[3
]}

Lutzny-Geier, Gloria ^{[4
]}

Klein-Hitpass, Ludger ^{[5
]}

Williamson, James C. ^{[6
]}

Lehner, Paul J. ^{[6
]}

Duerig, Jan ^{[7
]}

Moellmann, Michael ^{[7
]}

Raso-Barnett, Livia ^{[8
]}

Hughes, Katherine ^{[9
]}

Santoro, Antonella ^{[1
,2
]}

Mendez-Ferrer, Simon ^{[1
,2
,10
]}

Oostendorp, Robert A. J. ^{[3
]}

Zimber-Strobl, Ursula ^{[11
]}

Peschel, Christian ^{[3
,12
]}

Hodson, Daniel J. ^{[1
,2
]}

Schmidt-Supprian, Marc ^{[3
,12
]}

Ringshausen, Ingo ^{[1
,2
]}

机构：

[1] Univ Cambridge, MRC Cambridge Stem Cell Inst, Wellcome Trust, Cambridge CB2 0AH, England

[2] Univ Cambridge, Dept Haematol, Cambridge CB2 0AH, England

[3] Tech Univ Munich, Klinikum Rechts Isar, Dept Hematol & Med Oncol, D-81675 Munich, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Dept Internal Med Haematol & Oncol 5, D-91054 Erlangen, Germany

[5] Univ Duisburg Essen, Fac Med, Inst Cell Biol, D-45122 Essen, Germany

[6] Univ Cambridge, CIMR, Cambridge CB2 0XY, England

[7] Univ Duisburg Essen, Univ Hosp Essen, Dept Hematol, D-45122 Essen, Germany

[8] Cambridge Univ Hosp NHS Fdn Trust, HODS, Cambridge CB2 0QQ, England

[9] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England

[10] NHS Blood & Transplant, Cambridge CB2 0PT, England

[11] Helmholz Zentrum, Res Unit Gene Vectors, D-81377 Munich, Germany

[12] DKFZ, German Canc Consortium, D-69120 Heidelberg, Germany

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

HEMATOPOIETIC STEM-CELLS; STROMAL CELLS; ACTIVATION; CLL; PATHWAY; MOUSE; BETA; DYSREGULATION; RESISTANCE; INHIBITORS;

D O I：

10.1038/s41467-018-06069-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-beta mediated degradation of beta-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises beta-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.

引用

页数：17

共 44 条

[1] Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms [J].