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Comparative Study
. 2010 May 6;115(18):3756-62.
doi: 10.1182/blood-2009-11-251132. Epub 2010 Mar 3.

Occurrence of Minimal Change Nephrotic Syndrome in Classical Hodgkin Lymphoma Is Closely Related to the Induction of C-Mip in Hodgkin-Reed Sternberg Cells and Podocytes

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Free PMC article
Comparative Study

Occurrence of Minimal Change Nephrotic Syndrome in Classical Hodgkin Lymphoma Is Closely Related to the Induction of C-Mip in Hodgkin-Reed Sternberg Cells and Podocytes

Vincent Audard et al. Blood. .
Free PMC article

Abstract

It is currently considered that idiopathic minimal change nephrotic syndrome is an immune-mediated glomerular disease. Its association with classical Hodgkin lymphoma minimal change nephrotic syndrome (cHL-MCNS) suggests a molecular link, which remains to be elucidated. We analyzed the expression of cmaf inducing protein (c-mip) in lymphomatous tissues and kidney biopsy samples of patients with cHL-MCNS (n = 8) and in lymphomatous tissues of patients with isolated cHL (n = 9). Because c-mip affects the regulatory loop involving Fyn, we investigated possible structural defects in this signaling pathway, using laser capture microdissection, reverse transcription polymerase chain reaction, and Western blotting. We found that c-mip was selectively expressed in Hodgkin and Reed-Sternberg (HRS) cells and podocytes of patients with cHL-MCNS but is undetectable in patients with isolated cHL. We demonstrated that c-mip was specifically involved in the negative regulation of early proximal signaling through its interaction with phosphoprotein associated with glycosphingolipid-enriched microdomains and Fyn. We showed that the up-regulation of c-mip in cHL-MCNS was associated with a possible Fyn defect in HRS cells and podocytes. Moreover, we showed that c-mip was up-regulated in Fyn-deficient podocytes. c-mip may be a useful marker of cHL-MCNS and its induction reflects the dysregulation of proximal signaling.

Conflict of interest statement

Conflict of Interest Disclosures

We have no conflict of interest to disclose

Figures

Figure 1
Figure 1. C-mip is upregulated in the glomeruli of eight patients with cHL-MCNS
A, Upper panel, Representative in situ hybridization of c-mip transcript in serial sections from normal human kidney (NHK) and kidney biopsies of patients with I-MCNS and cHL-MCNS (ASP: antisense probe; SP: sense probe); B, Representative immunohistochemistry on serial sections of normal human kidney and kidney biopsies from patients with I-MCNS and cHL-MCNS (original magnification, X40). C-mip upregulation was detected in the podocytes of all patients with cHL-MCNS.
Figure 1
Figure 1. C-mip is upregulated in the glomeruli of eight patients with cHL-MCNS
A, Upper panel, Representative in situ hybridization of c-mip transcript in serial sections from normal human kidney (NHK) and kidney biopsies of patients with I-MCNS and cHL-MCNS (ASP: antisense probe; SP: sense probe); B, Representative immunohistochemistry on serial sections of normal human kidney and kidney biopsies from patients with I-MCNS and cHL-MCNS (original magnification, X40). C-mip upregulation was detected in the podocytes of all patients with cHL-MCNS.
Figure 2
Figure 2. Upregulation of c-mip in lymph nodes of eight patients with cHL-MCNS is restricted to Hodgkin and Reed-Sternberg (HRS) cells
A, Immunohistochemistry analysis of c-mip in normal lymphoid tissues (thymus, lymphoid follicle of the spleen and lymph nodes); note that c-mip is not seen in normal tissues, except in the transitional zone of node tissue and in the lymphoid follicle (indicated by arrows) (original magnification, X20); B, Representative image showing c-mip in lymphomatous tissues from two patients with isolated cHL (original magnification, X20) (HRS cells are indicated by arrows); note that c-mip is undetectable in lymphomatous tissues from isolated cHL; C, Representative expression of c-mip in lymphomatous tissues from two patients with cHL-MCNS (original magnification, X20). c-mip shows intense staining in cHL-MCNS, restricted to HRS cells. D, Localization of c-mip in HRS cells from four patients with cHL-MCNS; no staining was detected in the HRS cells of two patients with isolated cHL (original magnification, X100). C-mip upregulation in HRS cells was found in all patients with cHL-MCNS, whereas no immunostaining was observed for c-mip in 9 control cases with isolated cHL
Figure 2
Figure 2. Upregulation of c-mip in lymph nodes of eight patients with cHL-MCNS is restricted to Hodgkin and Reed-Sternberg (HRS) cells
A, Immunohistochemistry analysis of c-mip in normal lymphoid tissues (thymus, lymphoid follicle of the spleen and lymph nodes); note that c-mip is not seen in normal tissues, except in the transitional zone of node tissue and in the lymphoid follicle (indicated by arrows) (original magnification, X20); B, Representative image showing c-mip in lymphomatous tissues from two patients with isolated cHL (original magnification, X20) (HRS cells are indicated by arrows); note that c-mip is undetectable in lymphomatous tissues from isolated cHL; C, Representative expression of c-mip in lymphomatous tissues from two patients with cHL-MCNS (original magnification, X20). c-mip shows intense staining in cHL-MCNS, restricted to HRS cells. D, Localization of c-mip in HRS cells from four patients with cHL-MCNS; no staining was detected in the HRS cells of two patients with isolated cHL (original magnification, X100). C-mip upregulation in HRS cells was found in all patients with cHL-MCNS, whereas no immunostaining was observed for c-mip in 9 control cases with isolated cHL
Figure 2
Figure 2. Upregulation of c-mip in lymph nodes of eight patients with cHL-MCNS is restricted to Hodgkin and Reed-Sternberg (HRS) cells
A, Immunohistochemistry analysis of c-mip in normal lymphoid tissues (thymus, lymphoid follicle of the spleen and lymph nodes); note that c-mip is not seen in normal tissues, except in the transitional zone of node tissue and in the lymphoid follicle (indicated by arrows) (original magnification, X20); B, Representative image showing c-mip in lymphomatous tissues from two patients with isolated cHL (original magnification, X20) (HRS cells are indicated by arrows); note that c-mip is undetectable in lymphomatous tissues from isolated cHL; C, Representative expression of c-mip in lymphomatous tissues from two patients with cHL-MCNS (original magnification, X20). c-mip shows intense staining in cHL-MCNS, restricted to HRS cells. D, Localization of c-mip in HRS cells from four patients with cHL-MCNS; no staining was detected in the HRS cells of two patients with isolated cHL (original magnification, X100). C-mip upregulation in HRS cells was found in all patients with cHL-MCNS, whereas no immunostaining was observed for c-mip in 9 control cases with isolated cHL
Figure 2
Figure 2. Upregulation of c-mip in lymph nodes of eight patients with cHL-MCNS is restricted to Hodgkin and Reed-Sternberg (HRS) cells
A, Immunohistochemistry analysis of c-mip in normal lymphoid tissues (thymus, lymphoid follicle of the spleen and lymph nodes); note that c-mip is not seen in normal tissues, except in the transitional zone of node tissue and in the lymphoid follicle (indicated by arrows) (original magnification, X20); B, Representative image showing c-mip in lymphomatous tissues from two patients with isolated cHL (original magnification, X20) (HRS cells are indicated by arrows); note that c-mip is undetectable in lymphomatous tissues from isolated cHL; C, Representative expression of c-mip in lymphomatous tissues from two patients with cHL-MCNS (original magnification, X20). c-mip shows intense staining in cHL-MCNS, restricted to HRS cells. D, Localization of c-mip in HRS cells from four patients with cHL-MCNS; no staining was detected in the HRS cells of two patients with isolated cHL (original magnification, X100). C-mip upregulation in HRS cells was found in all patients with cHL-MCNS, whereas no immunostaining was observed for c-mip in 9 control cases with isolated cHL
Figure 3
Figure 3. C-mip interacts with PAG and Fyn in HRS cell lines
a, Western blot detection of c-mip protein in lysates from HRS and Jurkat cell lines. HEK cells were transfected with a c-mip expression plasmid and were used as positive controls. Immunoprecipitation of endogenous Fyn (b) and PAG/Cbp (c) from HRS cell lines co-transfected with the c-mip expression plasmid or empty vector (Ev).
Figure 4
Figure 4. Expression of Fyn signaling regulatory loop in human and rat glomeruli
The presence of Csk, Fyn and PAG was analyzed by Western blotting on glomerular extracts.
Figure 5
Figure 5. Absence of Fyn detection in lymphomatous tissue and in microdissected glomeruli from one patient with cHL-MCNS
a, Analysis of Fyn expression by RT-PCR in normal PBMC, in lymphomatous tissue from patient N° 8 and a control patient with isolated cHL, in the PBMC of two patients with an I-MCNS relapse and in HRS cell lines. b, Analysis of Fyn expression in microdissected glomeruli from the patient N° 8 and a control patient without glomerular disease. Notably, transcripts for FAT and neuropilin1 were easily detected in the microdissected glomeruli. c, Immunohistochemistry analysis of Fyn protein in normal human kidney (left panel) and in a kidney biopsy specimen from patient N° 8 (right panel). Note the absence of Fyn protein from podocytes of patient N° 8.
Figure 5
Figure 5. Absence of Fyn detection in lymphomatous tissue and in microdissected glomeruli from one patient with cHL-MCNS
a, Analysis of Fyn expression by RT-PCR in normal PBMC, in lymphomatous tissue from patient N° 8 and a control patient with isolated cHL, in the PBMC of two patients with an I-MCNS relapse and in HRS cell lines. b, Analysis of Fyn expression in microdissected glomeruli from the patient N° 8 and a control patient without glomerular disease. Notably, transcripts for FAT and neuropilin1 were easily detected in the microdissected glomeruli. c, Immunohistochemistry analysis of Fyn protein in normal human kidney (left panel) and in a kidney biopsy specimen from patient N° 8 (right panel). Note the absence of Fyn protein from podocytes of patient N° 8.
Figure 6
Figure 6. C-mip is upregulated in Fyn-deficient mice
Immunohistochemistry analysis of c-mip in serial sections from normal and Fyn-deficient mice kidneys (original magnification, X40).

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