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

Abstract

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)

Chronic lymphocytic leukemia: Time to go past genomics?

“…MYD88 missense mutations are activator type mutations that result in the constitutive activation of the NFjB and others signaling pathways [83]. In CLL, MYD88 mutations are associated with the IGHV-mutated status and del13q14, but prognostic significance of MYD88 mutations remains actually controversial [84,85]. Others actors of the TLR pathway leading to potential activation of the NF-jB signaling have been reported to be mutated in CLL and include TLR2, IRAK1/4 or TRAF6 [4,6,10] (Fig.…”

MYD88L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome

“…MYD88 has also been recurrently found mutated at different frequencies in several lymphoid neoplasms, including the majority of Waldenstr€ om macroglobulinemias (90%), in 69% of primary cutaneous leg-type DLBCL, in 38% to 50% of central nervous system lymphomas, in 9% of MALT lymphomas, and in approximately 3% of patients with chronic lymphocytic leukemia (CLL; refs. 11,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. MYD88 L265P mutation is the most frequent and most oncogenic form in DLBCL, although a gain of function triggering an increased production of chemokines has also been demonstrated for other variants (11,34,36).…”

“…Most likely, this is due to the fact that the different cellular pathways affected by MYD88 mutation have different relevance for cell survival according to the stage of B-cell maturation, the genetic/ epigenetic mechanisms involved in each type of tumor, and the tumor cell interaction with the microenvironment. Thus, CLL patients with mutated MYD88 show a favorable prognosis (35). In DLBCL, MYD88 mutations have been related to specific extranodal sites (particularly the so-called immune-privileged territories) and might be associated with unfavorable outcome (37).…”

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

“…12,15,22,23 In contrast, this abnormality has been found much less frequently in other small B-cell neoplasms, including 4-21% of cases diagnosed as splenic marginal zone lymphoma and 1-10% of chronic lymphocytic leukemia. 11,12,15,[23][24][25][26] The current study was designed to examine the morphologic correlates of MYD88 L265P in nodal and splenic small B-cell neoplasms with plasmacytic differentiation, and determine whether molecular studies for this mutation may assist in the diagnosis of lymphoplasmacytic lymphoma in routine practice. Figure 3 Four cases with MYD88 mutation (two originally classified as nodal marginal zone lymphoma with plasmacytic differentiation and two as small B-cell neoplasm with plasmacytic differentiation, not otherwise specified) showed similar features.…”

“…This case displayed a prominently nodular growth pattern and cytology that appeared much more consistent with a diagnosis of nodal marginal zone lymphoma with plasmacytic differentiation. MYD88 L265P has also been described in a small percentage of chronic lymphocytic leukemia/small lymphocytic lymphoma, 15,21,25,26,40,41 emphasizing that MYD88 mutation status alone clearly cannot be used to define lymphoplasmacytic lymphoma. The MYD88 L265P abnormality has also been reported in a small percentage of cases diagnosed as extranodal marginal zone lymphoma, 19,20 although distinction between extranodal marginal zone lymphoma with plasmacytic differentiation and an extranodal lymphoplasmacytic lymphoma may be somewhat arbitrary, and the prior studies included insufficient clinical or histologic information to completely exclude extranodal lymphoplasmacytic lymphoma.…”