MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia

Treon, Steven P.; Liu, Xu; Yang, Guang; Zhou, Yangsheng; Liu, Xia; Cao, Yang; Sheehy, Patricia; Manning, R.J.; Patterson, Christopher J.; Tripsas, Christina; Arcaini, Luca; Pinkus, Geraldine S.; Rodig, Scott J.; Sohani, Aliyah R.; Harris, Nancy L.; Laramie, Jason M.; Skifter, Donald A.; Lincoln, Stephen E.; Hunter, Zachary

doi:10.1056/nejmoa1200710

Cited by 1,136 publications

(947 citation statements)

References 34 publications

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“…11 Mutations of MYD88, including the L265P point mutation, had been previously described in diffuse Figure 2 Three cases of small B-cell neoplasm with plasmacytic differentiation, not otherwise specified, with MYD88 mutations displayed diffuse architectural effacement (a) by a monomorphic lymphoplasmacytic infiltrate (b) cytologically similar to that seen in classic lymphoplasmacytic lymphoma.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, next generation sequencing studies have identified a highly recurrent point mutation, MYD88 L265P, in 490% of cases of bone-marrow-based lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, [11][12][13][14][15][16] suggesting that this mutation may serve as a sensitive diagnostic marker for lymphoplasmacytic lymphoma. A previous study has suggested that detection of the MYD88 L265P abnormality can assist in classifying challenging bonemarrow-based B-cell neoplasms with plasmacytic differentiation.…”

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MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

et al. 2015

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The diagnosis of lymphoplasmacytic lymphoma is often challenging, especially in extramedullary tissues where the differential diagnosis includes nodal marginal zone lymphoma, splenic marginal zone lymphoma, or other small B-cell neoplasms with plasmacytic differentiation. The MYD88 L265P mutation has been recently identified in 490% of bone-marrow-based lymphoplasmacytic lymphoma, but the incidence of this abnormality and corresponding morphologic correlates in nodal lymphoplasmacytic lymphoma have not been established. We analyzed 87 cases of extramedullary lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, unclassifiable splenic B-cell lymphomas, nodal marginal zone lymphoma with plasmacytic differentiation, and chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation for MYD88 L265P. Eighteen cases (21%) were positive, including 9/9 (100%) lymphoplasmacytic lymphomas with classic histologic features, 5/12 (42%) cases that met 2008 WHO criteria for lymphoplasmacytic lymphoma but with atypical morphologic features, 3/15 (20%) cases initially considered nodal marginal zone lymphoma with plasmacytic differentiation, and 1/6 (17%) unclassifiable splenic B-cell lymphomas. The presence of MYD88 L265P was associated with IgM paraprotein (Po0.001) and a trend for bone marrow involvement (P ¼ 0.09). Each of 44 splenectomy-defined splenic marginal zone lymphomas (19 with plasmacytic differentiation) and the chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation were negative for the mutation. Morphologic re-review with knowledge of MYD88 mutation status and all available clinical features suggested all MYD88 mutated cases were consistent with lymphoplasmacytic lymphoma (either classic or variant histology), except for one case which remained most consistent with nodal marginal zone lymphoma with plasmacytic differentiation. These results demonstrate the importance of MYD88 mutational analysis in better defining lymphoplasmacytic lymphoma as a relatively monomorphic small B-cell lymphoma with plasmacytic differentiation that may show total nodal architectural effacement and follicular colonization. Cases previously considered lymphoplasmacytic lymphoma that are more polymorphous and are often associated with histiocytes should no longer be included in the lymphoplasmacytic lymphoma category. Clinicopathologic review suggests that although MYD88 mutated non-lymphoplasmacytic lymphoma small B-cell neoplasms exist, they are very uncommon.

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Section: Discussionmentioning

confidence: 98%

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MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

et al. 2015

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“…14,24,25 For instance, it was recently described that an oncogenic-activating mutation of MyD88 is responsible for the uncontrolled proliferation of cells from patients affected by lymphomas and Waldenström's macroglobulinemia, a subgroup of immunoglobulin M-secreting non-Hodgkin lymphomas. In both studies, treatment of patient cells with the MyD88 decoy epta-peptide strongly inhibited oncogenic proliferation in vitro, 13,14 which suggests that MyD88 inhibitors could be therapeutically suitable for these neoplastic diseases. This is particularly relevant for patients with Waldenström's macroglobulinemia, because a mutation of MyD88 was found in the large majority of patients affected by this neoplasia.…”

Section: Application Of Myd88 Inhibitors To Models Of Human Diseasesmentioning

confidence: 99%

“…9,10 Notably, MyD88 itself was shown to play a determinant role in the promotion of several human cancers, including blood malignancies such as lymphoma and chronic lymphocytic leukemia. [11][12][13][14][15] For these reasons, the TLR/IL-1R pathway has attracted considerable interest as a potential therapeutic target. 16,17 …”

Section: Introductionmentioning

confidence: 99%

Targeting the Toll-like Receptor/Interleukin 1 Receptor Pathway in Human Diseases: Rational Design of MyD88 Inhibitors

Loiarro

Ruggiero

Sette

2013

Clinical Lymphoma Myeloma and Leukemia

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Toll-like receptor (TLR)/interleukin (IL) 1 receptor (IL-1R) play a fundamental role in the immune response. These receptors are distributed in various cellular compartments and recognize different components of pathogens. All TLR/IL-1Rs, with the exception of TLR3, interact with MyD88, an intracellular adapter protein that triggers a signaling cascade that culminates in the expression of inflammatory genes. Because aberrant activation of TLR/IL-1Rs can promote the onset of inflammatory or autoimmune diseases and malignancies, this pathway has attracted considerable interest as a potential therapeutic target. Given the central role of MyD88 in TLR/IL-1R signaling, we set out different strategies to develop drugs that can block its function. Structural and functional analysis of the MyD88 domains allowed us to identify crucial residues required for MyD88 homodimerization. Moreover, we developed small cell-permeable peptides and peptidomimetic agents that inhibit MyD88 homodimerization and function. Our results pave the way for the development of new therapeutic drugs for the inhibition of MyD88-dependent signaling.

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“…43 Of interest diagnostically, it is found in only a small proportion of marginal zone lymphomas and CLL but present in about 90% of lymphoplasmacytic lymphomas, suggesting we may finally have a diagnostic tool with a high yield to help make the latter diagnosis. 35,43,44 The sequencing technologies can also be used to identify chromosomal translocations.…”

Section: Molecular Studiesmentioning

confidence: 99%

Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course

Swerdlow

2013

Modern Pathology

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MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia

Cited by 1,136 publications

References 34 publications

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

Targeting the Toll-like Receptor/Interleukin 1 Receptor Pathway in Human Diseases: Rational Design of MyD88 Inhibitors

Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course

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