MYD88 L265P Mutation in Lymphoid Malignancies

Abstract

Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis. is a driver gene found in hematologic B-cell malignancies. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ∼90% of Waldenström macroglobulinemia (WM) cases and in significant portions of activated B-cell diffuse large B-cell lymphomas and IgM monoclonal gammopathy of undetermined significance. Few cancers such as WM have a single amino acid substitution in one gene like MYD88 L265P that occurs in ∼90% of cases, making WM paradigmatic for study of a single causative mutation in oncogenesis. In this review, we summarize the frequency and cancer spectrum of MYD88 L265P and its downstream effects in lymphoid cancers. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell-independent antigens or in response to protein antigens before class switching. We also discuss therapeutic strategies that include targeting Bruton tyrosine kinase and other kinases, interfering with the assembly of MYD88 and its interacting partners, and L265P-specific peptide-based immunotherapy. .

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…In LPL/WM, a point mutation of MYD88 L265P is the most common "gain-of-function" somatic mutation, occurring in 80%-95% of LPL/WM [123]. In LPL/WM cells, however, mutated MYD88 transcriptionally upregulates hematopoietic cell kinase (HCK), which in turn activates BTK, as well as the ERK and AKT [124], Phospholipase C (PLC-γ), and interleukin-1 and interleukin-4 receptor associated kinases (IRAK1 and IRAK4, respectively) [125]. Similarly, CXCR4 mutations closely resemble those observed in WHIM patients, and have been observed in 27%-40% of patients with LPL/WM [126].…”

MYD88 in the driver’s seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications

“…The oncogenic activity of MYD88(L265P), as well as its high frequency in several B-NHL subtypes, ensure that MYD88 and its affiliated signaling pathways are very interesting for targeted therapeutic strategies. As reviewed by Yu et al 18 and Weber et al, 119 several targets are conceivable for direct or indirect inhibition, such as IRAK1 and IRAK4 in the myddosome-complex, TAK1 in downstream signaling, BTK in the BCR pathway, TLR9 in the My-T-BCR supercomplex, and components of the concurrently activated PI3K/AKT/mTOR and HCK pathways ( Figure 2).…”

“…Inhibition of BTK resulted in a decrease of the formation of this MYD88-BTK complex, but lacked effect on IRAK4/IRAK1 activity and vice versa, indicating a potential necessity of dual inhibition of IRAK and BTK for WM with MYD88(L265P). [16][17][18] MYD88 is frequently mutated in patients who also harbor a mutation in the 196 tyrosine residue in the ITAM domain of CD79B (NM_000626) and these patients seem to benefit most from BTK-inhibition treatment. 19 The exact consequence of these double mutations in B-NHL is unclear, but Phelan et al 8 recently provided new insight into the mechanism of combined MYD88 and BCR-pathway activation as they identified a MYD88-TLR9-BCR (My-T-BCR) supercomplex.…”

“…2,3,18, The highest prevalence of MYD88(L265P) is found in lymphoplasmacytic lymphoma/WM, with approximately 85% of the patients being affected. 18,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] In DLBCL, the prevalence of MYD88(L265P) is highest (range, 44% to 73%) in extranodal DLBCL, in immune-privileged sites, 96 such as primary DLBCL of the central nervous system 18,22,23,[86][87][88]96 and primary testicular lymphoma, 22,23,96,108 primary cutaneous DLBCL, leg type, 22,71,89-91 orbital/vitreoretinal DLBCL, 22,97,98 intravascular large B-cell lymphoma, 95 and primary breast DLBCL. 22,99 The high prevalence of MYD88(L265P) in extranodal site-specific lymphomas, lymphoplasmacytic lymphoma, and WM may provide an indication for the origin of these lymphomas.…”

“…This is supported by a recent study by our group that identified MYD88 mutations as an independent marker, in a cohort of 250 patients with DLBCL, in addition to the routinely used MYC and BCL2 and/or BCL6 rearrangements and Epstein-Barr virus status (according to the 2016 World Health Organization classification 110 ). 83 Furthermore, MYD88(L265P) is absent in primary mediastinal large Bcell lymphoma 2,3,94 and primary cutaneous follicle center lymphoma, [71][72][73] and rarely present in hairy cell leukemia (1.1%), 22,30,[57][58][59] plasma cell myeloma (1.5%), 18,22,23,43,106,107 Burkitt lymphoma (1.5%), 2,74 follicular lymphoma (1.9%), 18,22,23,67,68 and CLL (2.5%). 18,[22][23][24]28,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]…”