Activation of TAK1 by MYD88 L265P Drives Malignant B-cell Growth in Non-Hodgkin Lymphoma

Overview

Journal Blood Cancer J

Date 2014 Feb 18

PMID 24531446

Citations 38

Authors

S M Ansell

L S Hodge

F J Secreto

M Manske

E Braggio

T Price-Troska

S Ziesmer

Y Li

S H Johnson

S N Hart

J-P A Kocher

G Vasmatzis

A Chanan-Kahn

M Gertz

R Fonseca

A Dogan

J R Cerhan

A J Novak

Affiliations

Soon will be listed here.

Abstract

Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.

Citing Articles

Immunoglobulin class-switch recombination: Mechanism, regulation, and related diseases.

Liu J, Zhang K, Zhang X, Guan F, Zeng H, Kubo M MedComm (2020). 2024; 5(8):e662.

PMID: 39144468 PMC: 11322596. DOI: 10.1002/mco2.662.

Waldenström Macroglobulinemia - A State-of-the-Art Review: Part 1: Epidemiology, Pathogenesis, Clinicopathologic Characteristics, Differential Diagnosis, Risk Stratification, and Clinical Problems.

Bibas M, Sarosiek S, Castillo J Mediterr J Hematol Infect Dis. 2024; 16(1):e2024061.

PMID: 38984103 PMC: 11232678. DOI: 10.4084/MJHID.2024.061.

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients.

Ramirez-Perez S, Vekariya R, Gautam S, Reyes-Perez I, Drissi H, Bhattaram P Arthritis Res Ther. 2023; 25(1):180.

PMID: 37749630 PMC: 10519089. DOI: 10.1186/s13075-023-03145-0.

The NF-κB multidimer system model: A knowledge base to explore diverse biological contexts.

Mitchell S, Tsui R, Tan Z, Pack A, Hoffmann A Sci Signal. 2023; 16(776):eabo2838.

PMID: 36917644 PMC: 10195159. DOI: 10.1126/scisignal.abo2838.

In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma.

Taniguchi S, Matsui T, Kimura K, Funaki S, Miyamoto Y, Uchida Y Nat Commun. 2023; 14(1):143.

PMID: 36650150 PMC: 9845242. DOI: 10.1038/s41467-022-35701-8.

References

Morin R, Mendez-Lago M, Mungall A, Goya R, Mungall K, Corbett R . Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476(7360):298-303. PMC: 3210554. DOI: 10.1038/nature10351. View

Landgren O, Staudt L . MYD88 L265P somatic mutation in IgM MGUS. N Engl J Med. 2012; 367(23):2255-6. DOI: 10.1056/NEJMc1211959. View

Vasmatzis G, Johnson S, Knudson R, Ketterling R, Braggio E, Fonseca R . Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012; 120(11):2280-9. PMC: 5070713. DOI: 10.1182/blood-2012-03-419937. View

Ngo V, Young R, Schmitz R, Jhavar S, Xiao W, Lim K . Oncogenically active MYD88 mutations in human lymphoma. Nature. 2010; 470(7332):115-9. PMC: 5024568. DOI: 10.1038/nature09671. View

Treon S, Xu L, Yang G, Zhou Y, Liu X, Cao Y . MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med. 2012; 367(9):826-33. DOI: 10.1056/NEJMoa1200710. View

Puente X, Pinyol M, Quesada V, Conde L, Ordonez G, Villamor N . Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011; 475(7354):101-5. PMC: 3322590. DOI: 10.1038/nature10113. View

Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V . Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011; 471(7337):189-95. PMC: 3271441. DOI: 10.1038/nature09730. View

Wu J, Powell F, Larsen N, Lai Z, Byth K, Read J . Mechanism and in vitro pharmacology of TAK1 inhibition by (5Z)-7-Oxozeaenol. ACS Chem Biol. 2013; 8(3):643-50. DOI: 10.1021/cb3005897. View

Elsawa S, Novak A, Ziesmer S, Almada L, Hodge L, Grote D . Comprehensive analysis of tumor microenvironment cytokines in Waldenstrom macroglobulinemia identifies CCL5 as a novel modulator of IL-6 activity. Blood. 2011; 118(20):5540-9. PMC: 3217355. DOI: 10.1182/blood-2011-04-351742. View

10.

Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X . IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B. J Biol Chem. 2001; 276(45):41661-7. DOI: 10.1074/jbc.M102262200. View

11.

Feldman A, Dogan A, Smith D, Law M, Ansell S, Johnson S . Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 2010; 117(3):915-9. PMC: 3035081. DOI: 10.1182/blood-2010-08-303305. View

12.

Jimenez C, Sebastian E, Chillon M, Giraldo P, Mariano Hernandez J, Escalante F . MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström's macroglobulinemia. Leukemia. 2013; 27(8):1722-8. DOI: 10.1038/leu.2013.62. View

13.

Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K . TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell. 2000; 5(4):649-58. DOI: 10.1016/s1097-2765(00)80244-0. View

14.

Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler O, Siebert R, Deckert M . Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol. 2011; 122(6):791-2. DOI: 10.1007/s00401-011-0891-2. View

15.

Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M, Shen Q . BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell. 2010; 18(6):568-79. PMC: 3030476. DOI: 10.1016/j.ccr.2010.10.030. View

16.

Xu L, Hunter Z, Yang G, Zhou Y, Cao Y, Liu X . MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood. 2013; 121(11):2051-8. PMC: 3596964. DOI: 10.1182/blood-2012-09-454355. View

17.

Schop R, Van Wier S, Xu R, Ghobrial I, Ahmann G, Greipp P . 6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance. Cancer Genet Cytogenet. 2006; 169(2):150-3. DOI: 10.1016/j.cancergencyto.2006.04.009. View

18.

Gupta M, Han J, Stenson M, Maurer M, Wellik L, Hu G . Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Blood. 2012; 119(12):2844-53. PMC: 3327462. DOI: 10.1182/blood-2011-10-388538. View

19.

Schop R, Jalal S, Van Wier S, Ahmann G, Bailey R, Kyle R . Deletions of 17p13.1 and 13q14 are uncommon in Waldenström macroglobulinemia clonal cells and mostly seen at the time of disease progression. Cancer Genet Cytogenet. 2002; 132(1):55-60. DOI: 10.1016/s0165-4608(01)00526-x. View

20.

Schuman J, Chen Y, Podd A, Yu M, Liu H, Wen R . A critical role of TAK1 in B-cell receptor-mediated nuclear factor kappaB activation. Blood. 2009; 113(19):4566-74. PMC: 2680363. DOI: 10.1182/blood-2008-08-176057. View