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Open Access 11-04-2024 | Primary Myelofibrosis | ORIGINAL ARTICLE

CCN2/CTGF expression does not correlate with fibrosis in myeloproliferative neoplasms, consistent with noncanonical TGF-β signaling driving myelofibrosis

Authors: Roos J. Leguit, Roel Broekhuizen, Moniek de Witte, Reinier A. P. Raymakers, Roel Goldschmeding

Published in: Virchows Archiv | Issue 5/2024

Abstract

The classical BCR::ABL1-negative myeloproliferative neoplasms (MPN) form a group of bone marrow (BM) diseases with the potential to progress to acute myeloid leukemia or develop marrow fibrosis and subsequent BM failure. The mechanism by which BM fibrosis develops and the factors that drive stromal activation and fibrosis are not well understood. Cellular Communication Network 2 (CCN2), also known as CTGF (Connective Tissue Growth Factor), is a profibrotic matricellular protein functioning as an important driver and biomarker of fibrosis in a wide range of diseases outside the marrow. CCN2 can promote fibrosis directly or by acting as a factor downstream of TGF-β, the latter already known to contribute to myelofibrosis in MPN.

To study the possible involvement of CCN2 in BM fibrosis in MPN, we assessed CCN2 protein expression by immunohistochemistry in 75 BM biopsies (55 × MPN and 20 × normal controls). We found variable expression of CCN2 in megakaryocytes with significant overexpression in a subgroup of 7 (13%) MPN cases; 4 of them (3 × essential thrombocytemia and 1 × prefibrotic primary myelofibrosis) showed no fibrosis (MF-0), 2 (1 × post-polycythemic myelofibrosis and 1 × primary myelofibrosis) showed moderate fibrosis (MF-2), and 1 (primary myelofibrosis) severe fibrosis (MF-3). Remarkably, CCN2 expression did not correlate with fibrosis or other disease parameters such as platelet count or thrombovascular events, neither in this subgroup nor in the whole study group. This suggests that in BM of MPN patients other, CCN2-independent pathways (such as noncanonical TGF-β signaling) may be more important for the development of fibrosis.

Gangat N, Tefferi A (2020) Myelofibrosis biology and contemporary management. Br J Haematol 191:152–170. https://doi.org/10.1111/bjh.16576CrossRefPubMed

Chen Z, Zhang N, Chu HY, Yu Y, Zhang ZK, Zhang G, Zhang BT (2020) Connective tissue growth factor: from molecular understandings to drug discovery Front Cell. Dev Biol 8:593269. https://doi.org/10.3389/fcell.2020.593269CrossRef

Blom IE, van Dijk AJ, Wieten L, Duran K, Ito Y, Kleij L, deNichilo M, Rabelink TJ, Weening JJ, Aten J (2001) In vitro evidence for differential involvement of CTGF, TGFbeta, and PDGF-BB in mesangial response to injury. Nephrol Dial Transplant 16:1139–1178CrossRefPubMed

Brunner A, Chinn J, Neubauer M, Purchio AF (1991) Identification of a gene family regulated by transforming growth factor-beta. DNA Cell Biol 10:293–300. https://doi.org/10.1089/dna.1991.10.293CrossRefPubMed

Grotendorst GR, Okochi H, Hayashi N (1996) A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ 7:469–480PubMed

Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A (2001) CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 276:10594–10601. https://doi.org/10.1074/jbc.M010149200CrossRefPubMed

Igarashi A, Okochi H, Bradham DM, Grotendorst GR (1993) Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell 4:637–645CrossRefPubMedPubMedCentral

Yang DH, Kim HS, Wilson EM, Rosenfeld RG, Oh Y (1998) Identification of glycosylated 38-kDa connective tissue growth factor (IGFBP-related protein 2) and proteolytic fragments in human biological fluids, and up-regulation of IGFBP-rP2 expression by TGF-beta in Hs578T human breast cancer cells. J Clin Endocrinol Metab 83:2593–2596. https://doi.org/10.1210/jcem.83.7.5097CrossRefPubMed

Leguit RJ, Raymakers RAP, Hebeda KM, Goldschmeding R (2021) CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis. J Cell Commun Signal 15:25–56. https://doi.org/10.1007/s12079-020-00602-2CrossRefPubMedPubMedCentral

10.

Vorwerk P, Wex H, Hohmann B, Oh Y, Rosenfeld RG, Mittler U (2000) CTGF (IGFBP-rP2) is specifically expressed in malignant lymphoblasts of patients with acute lymphoblastic leukaemia (ALL). Br J Cancer 83:756–760. https://doi.org/10.1054/bjoc.2000.1364CrossRefPubMedPubMedCentral

11.

Battula VL, Le PM, Sun JC, Nguyen K, Yuan B, Zhou X, Sonnylal S, McQueen T, Ruvolo V, Michel KA, Ling X, Jacamo R, Shpall E, Wang Z, Rao A, Al-Atrash G, Konopleva M, Davis RE, Harrington MA, Cahill CW, Bueso-Ramos C, Andreeff M (2017) AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth. JCI Insight 2. https://doi.org/10.1172/jci.insight.90036

12.

Li H, Li J, Cheng J, Chen X, Zhou L, Li Z (2019) AML-derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562-ADM fusiform transformation and chemoresistance. Oncol Rep 42:1035–1046. https://doi.org/10.3892/or.2019.7237CrossRefPubMedPubMedCentral

13.

Shergill A, Saraf SL, Gaitonde S, Rondelli D, Khan I (2015) CCN2 - Exploring a new biomarker in myelofibrosis. Blood 126:4063–4063. https://doi.org/10.1182/blood.V126.23.4063.4063CrossRef

14.

Astrom M, Hahn-Stromberg V, Zetterberg E, Vedin I, Merup M, Palmblad J (2015) X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis. Am J Hematol 90:E44-48. https://doi.org/10.1002/ajh.23907CrossRefPubMed

15.

Cicha I, Garlichs CD, Daniel WG, Goppelt-Struebe M (2004) Activated human platelets release connective tissue growth factor. Thromb Haemost 91:755–760. https://doi.org/10.1160/TH03-09-0602CrossRefPubMed

16.

Thiele J, Kvasnicka HM (2006) Myelofibrosis in chronic myeloproliferative disorders–dynamics and clinical impact. Histol Histopathol 21:1367–1378. https://doi.org/10.14670/HH-21.1367CrossRefPubMed

17.

Mizutani M, Ito Y, Mizuno M, Nishimura H, Suzuki Y, Hattori R, Matsukawa Y, Imai M, Oliver N, Goldschmeding R, Aten J, Krediet RT, Yuzawa Y, Matsuo S (2010) Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate. Am J Physiol Renal Physiol 298:F721-733. https://doi.org/10.1152/ajprenal.00368.2009CrossRefPubMed

18.

Rayego-Mateos S, Morgado-Pascual JL, Lavoz C, Rodrigues-Diez RR, Marquez-Exposito L, Tejera-Munoz A, Tejedor-Santamaria L, Rubio-Soto I, Marchant V, Ruiz-Ortega M (2022) CCN2 binds to tubular epithelial cells in the kidney. Biomolecules 12. https://doi.org/10.3390/biom12020252

19.

Yao JC, Oetjen KA, Wang T, Xu H, Abou-Ezzi G, Krambs JR, Uttarwar S, Duncavage EJ, Link DC (2022) TGF-beta signaling in myeloproliferative neoplasms contributes to myelofibrosis without disrupting the hematopoietic niche. J Clin Invest 132. https://doi.org/10.1172/JCI154092

20.

Melo-Cardenas J, Migliaccio AR, Crispino JD (2021) The role of megakaryocytes in myelofibrosis. Hematol Oncol Clin North Am 35:191–203. https://doi.org/10.1016/j.hoc.2020.11.004CrossRefPubMedPubMedCentral

21.

Zhan H, Kaushansky K (2022) Megakaryocytes as the regulator of the hematopoietic vascular niche Front. Oncol 12:912060. https://doi.org/10.3389/fonc.2022.912060CrossRef

22.

Cunin P, Nigrovic PA (2019) Megakaryocytes as immune cells. J Leukoc Biol 105:1111–1121. https://doi.org/10.1002/JLB.MR0718-261RRCrossRefPubMed

23.

Sogo S, Matsumura-Takeda K, Isakari Y, Harada Y, Nishioka K, Kawakami T, Ono T, Taki T (2005) Identification of new megakaryocytic subpopulations in mouse bone marrow. Blood 106:2265–2265. https://doi.org/10.1182/blood.V106.11.2265.2265CrossRef

24.

Sun S, Jin C, Si J, Lei Y, Chen K, Cui Y, Liu Z, Liu J, Zhao M, Zhang X, Tang F, Rondina MT, Li Y, Wang QF (2021) Single-cell analysis of ploidy and the transcriptome reveals functional and spatial divergency in murine megakaryopoiesis. Blood 138:1211–1224. https://doi.org/10.1182/blood.2021010697CrossRefPubMedPubMedCentral

25.

de Winter P, Leoni P, Abraham D (2008) Connective tissue growth factor: structure-function relationships of a mosaic, multifunctional protein. Growth Factors 26:80–91. https://doi.org/10.1080/08977190802025602CrossRefPubMed

26.

Jun JI, Lau LF (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 10:945–963. https://doi.org/10.1038/nrd3599CrossRefPubMedPubMedCentral

27.

Takigawa M (2018) An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin. J Cell Commun Signal 12:253–264. https://doi.org/10.1007/s12079-017-0414-6CrossRefPubMed

28.

Leask A (2020) Slow train coming: an anti-CCN2 strategy reverses a model of chronic overuse muscle fibrosis. J Cell Commun Signal 14:349–350. https://doi.org/10.1007/s12079-020-00568-1CrossRefPubMedPubMedCentral

29.

Perbal B (2018) The concept of the CCN protein family revisited: a centralized coordination network. J Cell Commun Signal 12:3–12. https://doi.org/10.1007/s12079-018-0455-5CrossRefPubMedPubMedCentral

30.

Ramazani Y, Knops N, Elmonem MA, Nguyen TQ, Arcolino FO, van den Heuvel L, Levtchenko E, Kuypers D, Goldschmeding R (2018) Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol 68–69:44–66. https://doi.org/10.1016/j.matbio.2018.03.007CrossRefPubMed

Title: CCN2/CTGF expression does not correlate with fibrosis in myeloproliferative neoplasms, consistent with noncanonical TGF-β signaling driving myelofibrosis
Authors: Roos J. Leguit
Roel Broekhuizen
Moniek de Witte
Reinier A. P. Raymakers
Roel Goldschmeding
Publication date: 11-04-2024
Publisher: Springer Berlin Heidelberg
Keywords: Primary Myelofibrosis
Primary Myelofibrosis
Published in: Virchows Archiv / Issue 5/2024
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-024-03799-4

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CCN2/CTGF expression does not correlate with fibrosis in myeloproliferative neoplasms, consistent with noncanonical TGF-β signaling driving myelofibrosis

Abstract

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Abstract

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