PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma

被引：9

作者：

Alonso, I. Garces de los Fayos ^{[1
,2
]}

Zujo, L. ^{[1
,2
,3
]}

Wiest, I ^{[1
,2
,3
]}

Kodajova, P. ^{[2
]}

Timelthaler, G. ^{[4
]}

Edtmayer, S. ^{[5
]}

Zrimsek, M. ^{[1
]}

Kollmann, S. ^{[6
]}

Giordano, C. ^{[1
]}

Kothmayer, M. ^{[1
,2
,7
]}

Neubauer, H. A. ^{[8
]}

Dey, S. ^{[9
,10
]}

Schlederer, M. ^{[1
]}

Schmalzbauer, B. S. ^{[2
,6
]}

Limberger, T. ^{[1
,3
,11
]}

Probst, C. ^{[1
,2
,3
]}

Pusch, O. ^{[7
]}

Hogler, S. ^{[2
]}

Tangermann, S. ^{[2
]}

Merkel, O. ^{[1
]}

Schiefer, A., I ^{[1
]}

Kornauth, C. ^{[12
,13
]}

Prutsch, N. ^{[14
]}

Zimmerman, M. ^{[14
]}

Abraham, B. ^{[15
]}

Anagnostopoulos, J. ^{[16
,17
]}

Quintanilla-Martinez, L. ^{[18
,19
]}

Mathas, S. ^{[20
,21
,22
,23
]}

Wolf, P. ^{[9
]}

Stoiber, D. ^{[5
]}

Staber, P. B. ^{[12
,13
]}

Egger, G. ^{[1
,13
,24
]}

Klapper, W. ^{[25
,26
]}

Woessmann, W. ^{[27
]}

Look, T. A. ^{[14
]}

Gunning, P. ^{[28
,29
]}

Turner, S. D. ^{[30
,31
]}

Moriggl, R. ^{[8
]}

Lagger, S. ^{[2
]}

Kenner, L. ^{[1
,2
,3
,10
,11
,32
]}

机构：

[1] Med Univ Vienna, Dept Pathol, A-1090 Vienna, Austria

[2] Univ Vet Med Vienna, Unit Lab Anim Pathol, A-1210 Vienna, Austria

[3] Med Univ Vienna, Div Nucl Med, A-1090 Vienna, Austria

[4] Med Univ Vienna, Ctr Canc Res, A-1090 Vienna, Austria

[5] Karl Landsteiner Univ Hlth Sci, Dept Pharmacol Physiol & Microbiol, Div Pharmacol, A-3500 Krems, Austria

[6] Univ Vet Med Vienna, Inst Pharmacol & Toxicol, A-1210 Vienna, Austria

[7] Med Univ Vienna, Ctr Anat & Cell Biol, A-1090 Vienna, Austria

[8] Univ Vet Med Vienna, Inst Anim Breeding & Genet, Unit Funct Canc Genom, A-1210 Vienna, Austria

[9] Med Univ Graz, Dept Dermatol, A-8036 Graz, Austria

[10] Med Univ Graz, Ctr Med Res ZMF, A-8010 Graz, Austria

[11] Med Univ Vienna, CBMed Core Lab, A-1090 Vienna, Austria

[12] Med Univ Vienna, Dept Med 1, Div Hematol & Hemostaseol, A-1090 Vienna, Austria

[13] Med Univ Vienna, Vienna Gen Hosp, Comprehens Canc Ctr Vienna, A-1090 Vienna, Austria

[14] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[15] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[16] Univ Wurzburg, Inst Pathol, D-97080 Wurzburg, Germany

[17] Charite Med Univ Berlin, Inst Pathol, D-10117 Berlin, Germany

[18] Univ Tubingen, Inst Pathol & Neuropathol, D-72076 Tubingen, Germany

[19] Univ Tubingen, Cluster Excellence iFIT, Image Guided & Funct Instructed Tumor Therapy, D-72076 Tubingen, Germany

[20] Charite Med Univ Berlin, Dept Hematol Oncol & Canc Immunol, D-12200 Berlin, Germany

[21] German Canc Res Ctr, German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[22] Max Delbruck Ctr MDC Mol Med, D-13125 Berlin, Germany

[23] Expt & Clin Res Ctr, D-13125 Berlin, Germany

[24] Boltzmann Inst Appl Diagnost, A-1090 Vienna, Austria

[25] Univ Kiel, Dept Pathol, Hematopathol Sect, Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany

[26] Univ Kiel, Univ Hosp Schleswig Holstein, Lymph Node Registry, D-24105 Kiel, Germany

[27] Univ Hosp Hamburg Eppendorf, Pediat Hematol & Oncol, Hamburg, Germany

[28] Univ Toronto Mississauga, Dept Chem & Phys Sci, Mississauga, ON L5L 1C6, Canada

[29] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada

[30] Univ Cambridge, Dept Pathol, Div Cellular & Mol Pathol, Cambridge CB2 0QQ, England

[31] Masaryk Univ, Cent European Inst Technol CEITEC, Brno, Czech Republic

[32] Med Univ Vienna, Christian Doppler Lab Appl Metabol, Dept Biomed Imaging & Image Guided Therapy, A-1090 Vienna, Austria

来源：

MOLECULAR CANCER | 2022年 / 21卷 / 01期

基金：

欧盟地平线“2020”; 奥地利科学基金会;

关键词：

ALCL; PDGFR beta; STAT3; STAT5A; STAT5B; NPM-ALK; Apoptosis; NPM-ALK; DNA METHYLATION; GENE-EXPRESSION; CANCER; CHEMOTHERAPY; DIFFERENTIATION; STAT3; CHILDREN; THERAPY; SAFETY;

D O I：

10.1186/s12943-022-01640-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFR beta. Blocking PDGFR beta kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. Methods and results: In a transgenic mouse model that mimics PDGFR beta-driven human ALCL in vivo, we identify PDGFR beta as a driver of aggressive tumor growth. Mechanistically, PDGFR beta induces the pro-survival factor Bcl-x(L) and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. Conclusions: We therefore propose PDGFR beta as a novel biomarker and introduce PDGFR beta-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFR beta or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK(+) ALCL patients.

引用

页数：19

共 63 条

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