Abstract
MYD88 mutations in chronic lymphocytic leukemia (CLL) are not well characterized. Earlier reports yielded conflicting results in terms of clinicopathologic presentation and prognostic impact of MYD88 mutations in CLL patients. In addition, the morphological and immunophenotypic features of CLL cases carrying MYD88 mutations have not been explored. Finally, the clinical or biologic implications of the canonical L265P MYD88 mutation vs. mutations in other sites of MYD88 within the context of CLL are also unknown. In this study, a cohort of 1779 CLL patients underwent mutational analysis, and 56 (3.1%) cases were found to have MYD88 mutations, including 38 with L265P mutations (designated here as group A) and 18 with non-L265P mutations (group B). Cases with wild type MYD88 were included as controls. There was no morphological difference in cases with and without MYD88 mutations. Immunophenotypically, cases with mutated MYD88 (both groups A and B) more frequently had an atypical immunophenotype when compared to wild type cases. Group A patients were younger and were associated with variable favorable prognostic factors, including less elevated β2-microglobulin level, negative CD38 and ZAP70, higher frequency of mutated IGHV and isolated del(13q14.3), and lower frequency of del(11q22.3) and mutations of NOTCH1 and SF3B1. In contrast, group B patients were more similar to CLL patients with wild type MYD88. There was no difference in time to first treatment when comparing MYD88-mutated vs. wild type CLL patients before and after stratification according to IGHV mutation status. In summary, MYD88 mutations are uncommon in CLL and cases with L265P mutation have distinctive clinical, immunophenotypic, cytogenetic, and molecular features. There is no significant impact of MYD88 mutations on time to first treatment in CLL.
Highlights
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a neoplasm of mature clonal B cells mutation status, ZAP-70 and CD38 expression levels, Shuai et al Blood Cancer Journal (2020)10:86 deletion 11q, deletion 17p, isolated deletion 13q, and various genetic mutations[4,5,6,7,8,9,10,11,12]
When we stratified cases into two groups based on mutation sites (i.e., L265P vs. non-L265P), we found that the L265P mutation was identified in younger patients, whereas other mutations were not (Table 1)
In the study by Martinez-Trillos et al the authors found that Toll-like receptor (TLR)/Myeloid differentiation primary response 88 (MYD88)-mutated chronic lymphocytic leukemia (CLL) was seen in a group of young patients with advanced stage at presentation, associated with mutated immunoglobulin heavy chain variable region (IGHV), with less ZAP-70 and CD38 expressions and a better OS23
Summary
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a neoplasm of mature clonal B cells mutation status, ZAP-70 and CD38 expression levels, Shuai et al Blood Cancer Journal (2020)10:86 deletion 11q, deletion 17p, isolated deletion 13q, and various genetic mutations[4,5,6,7,8,9,10,11,12]. Mutations in different signaling pathways have been identified in CLL, some of which are associated with prognosis. Mutations in TP53, ATM, NOTCH1, SF3B1, and BIRC3 are associated with a poorer outcome[13,14,15]. Myeloid differentiation primary response 88 (MYD88) mutations have been described uncommonly in CLL and their prognostic impact is not clearly defined. MYD88 is located on chromosome 3p22.2 and encodes an adapter protein that recruits interleukin 1 receptorassociated kinase 4 (IRAK4). The MYD88:IRAK4 complex recruits the IRAK4 substrate IRAK2 or the related IRAK1, forming critical signaling mediators of the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily[16]. The MYD88 L265P mutant is involved in spontaneously assembling the myddosome complexes, which in turn leads to NF-kB signaling activation, JAK kinase activation of STAT3, and secretion of cytokines[17]
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