MYD88 Somatic Mutation Is a Genetic Feature of Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Pham‐Ledard, Anne; Cappellen, David; Martínez, Fredy Hermógenes Prada; Vergier, Béatrice; Beylot‐Barry, M.; Merlio, Jean-Philippe

doi:10.1038/jid.2012.102

Cited by 90 publications

(70 citation statements)

References 16 publications

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“…Out of these 23 patients, 18 had already been included in previous studies about primary cutaneous large B-cell lymphoma, leg type by our team or by the French study group of cutaneous lymphoma. 3,14,22 Histological and Immunohistochemistry Data Sections (3-mm thick) of formalin-fixed paraffinembebbed skin biopsies were stained with BCL2 (clone 124, DAKO, Les Ulis, France), IRF4/MUM1 (clone mum1p, DAKO), BCL6 (clone PGB6P, DAKO), CD10 (clone 56C6, NOVOCASTRA, Leica, Nanterre, France), and c-MYC (clone Y69, EPITOMICS, Burlingame, CA). The cutoff for tumor positivity was set at 30% of tumor cells staining for each antibody, 5,12,34 except for c-MYC (nuclear staining in 450% of tumor cells).…”

Section: Patient Selectionmentioning

confidence: 99%

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

et al. 2014

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Primary cutaneous large B-cell lymphoma, leg type has been individualized from nodal diffuse large B-cell lymphoma. The objective of this study was to screen primary cutaneous large B-cell lymphoma, leg type for genetic alterations recently described in nodal diffuse large B-cell lymphoma. Skin biopsies from 23 patients were analyzed for IRF4, BCL2, BCL6, and MYC expression. FISH testing was performed for BCL2, BCL6, MYC with separation probes and for CDKN2A and PRDM1/BLIMP1 deletion. Multiple sequential FISH analyses with up to six probes were performed to define samples with multiple cytogenetic alterations. MYD88 mutations were studied by Sanger sequencing. All cases but one displayed at least one genetic alteration (96%). Nine patients exhibited a single genetic mutation and 12 combined several alterations (52%). We observed a split for BCL2, BCL6, or MYC in 1/23, 6/23, and 3/23 of cases, respectively. No double-hit lymphoma was observed. CDKN2A deletion was detected by FISH in only 5/23 cases. BLIMP1 and/or 6q deletion was observed at a higher rate in 10/20 of cases. No correlation between rearrangement and immunohistochemical expression was found for BCL2 or MYC. FISH tracking of sequential hybridizations showed that several alterations were carried by the same nuclei. The p.L265P MYD88 mutation was found in 11/18 (61%) of cases. Contrary to most cutaneous lymphomas that rarely harbor primary genetic alteration of their nodal histological equivalent, primary cutaneous large B-cell lymphoma, leg type seems to be a 'cutaneous counterpart' of activated B-cell-like diffuse large B-cell lymphoma with a similar cytogenetic profile and a high rate of MYD88 oncogenic L265P mutation. This also suggests a common lymphomagenesis with NF-jB activation, strong IRF4 expression and terminal B-cell differentiation blockage. Our data support the use of therapies targeting NF-jB, as most patients displayed disease progression and resistance to conventional therapies.

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Section: Patient Selectionmentioning

confidence: 99%

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

et al. 2014

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“…MYD88 (L265P) was absent in normal paired tissues from WM/LPL patients and in healthy donor B cells, and it was absent or rarely expressed in samples from multiple myeloma, marginal zone lymphoma (MZL) or IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) patients. A heterozygous mutation of exon 5 in the MYD88 gene has been previously reported in a substantial proportion of activated B-cell-like subtype diffuse large B-cell lymphomas, 14 as well as in primary cutaneous and primary central nervous system diffuse large B-cell lymphomas 15,16 and in a minority of cases of chronic lymphocytic leukemia. 6,17 The single amino-acid mutation in the MYD88 gene affects the Toll/IL-1 receptor domain of adaptor protein MYD88, and it favors tumor-cell survival through IRAK1 (interleukin-1 receptor associated kinase)/IRAK4, and NF-kB (nuclear factor k-light-chain-enhancer of activated B cells) signaling.…”

Section: Introductionmentioning

confidence: 99%

Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenström’s macroglobulinemia and related lymphoid neoplasms

Varettoni¹,

Arcaini

Zibellini³

et al. 2013

Blood

292

225

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“…MYD88 has been found recurrently mutated in different lymphoproliferative disorders, [15][16][17][18] including in approximately 3% of patients with CLL. 8,10 MYD88 is an adaptor protein of the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) that has a role in innate immune response and plays a crucial role in the homeostasis of human B cells.…”

Section: Introductionmentioning

confidence: 99%

Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome

Martínez‐Trillos

Pinyol

Navarro

et al. 2014

Blood

104

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Key Points• Mutations in the TLR/MYD88 pathway occur in 4% of patients with CLL, and they are the most frequent in young patients.• TLR/MYD88 mutations in CLL patients confer a good outcome, which is similar to that of the age-and gendermatched healthy population.Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor kB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age £50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P 5 .002), and in the subset of patients age £50 years (100% vs 70%; P 5 .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age-and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome. (Blood. 2014;123(24):3790-3796)

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MYD88 Somatic Mutation Is a Genetic Feature of Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Cited by 90 publications

References 16 publications

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenström’s macroglobulinemia and related lymphoid neoplasms

Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome

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