MYD 88 Mutation

MYD88 gene is as an important oncogenic driver in B-cell lymphomas

Wirkungsprinzip

MYD88 mutations hotspot: MYD88(L265P) constitutively activate NF-κB and its associated signaling pathways, thereby promoting B-cell proliferation and survival.

Haeufigkeit

  • Morbus Waldenström - 90%
  • extranodale diffus large cell Lympoma / ZNS,Haut,.. / ABC like

Auswirkungen

  • Prognose
  • extranodale diffus large cell Lympoma / ZNS,Haut,.. / ABC like

Physiologie MYD88

In normal physiology, MYD88 acts as a signaling adaptor in the canonical NF-κB pathway (Figure 1). This pathway is activated upon recognition of pathogen-associated molecular patterns (PAMP)- Bestandteile von Mikroorgansimen - by receptors containing a toll/interleukin-1 receptor (TIR) domain, such as toll-like receptors (TLR) and the interleukin receptors 1 (IL-1R) and 18 (IL-18R). Prinzipiell teil einer unspezifischen Aktivierung des lymphatischen Systems.

Die Aktivierung führt zur Bildung des mydosom-Komplexes indem MYD88 IRAK4 beide aktivieren IRAK1/2 und diese aktivieren TRAF - TumorNekroseFaktor6 / IRAK=InterkeukinRezeptorAktivitated Kinase.

über TAK1 erfolgt die Aktivierung von MAPK sowie die Hydolyse des NFkappa Inhibitors wodurch NFkappaB freigesetzt wird und in den Zellkern gelangt.

Die L256P Mutation führt zu einer vermehrten Aktivierung von MYD88

BCR und MYD88

In addition to the canonical NF-κB pathway, the BCR pathway plays an important role in B-cell survival and proliferation and oncogenesis of B-NHL with MYD88 mutations

BTK is an integral protein in the BCR signaling cascade and has been found to be preferentially complexed to MYD88 in WM cells with MYD88(L265P) and not in MYD88 wildtype cells. 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)

Die Mutation triggert auch die BTK, sodass bei Patienten mit MYD88 + CXCR4 Wildtyp das Ansprechen auf Ibrutinib schlecht ist.

NF-κB not only activates the transcription of genes involved in cell survival and proliferation, but also results in autocrine signaling with IL-6 and IL-10.

Häufigkeit bei versch. Lymphomen

Prognose

275 DLBCL patients, showed that DLBCL patients with MYD88(L265P) had a statistically significant inferior overall survival compared with DLBCL patients with wildtype MYD88.

In other subtypes of B-NHL, such as CLL, splenic marginal zone lymphoma, and WM, MYD88(L265P9 is associated with a superior survival compared with wildtype MYD88.In WM, approximately 30-40% of patients present with concomitantly mutated MYD88 and CXCR4, a gene involved in homing of B cells in the bone marrow, and these patients present with a greater disease burden and reduced progression-free

With regards to CLL, Improgo et al.39 stated that MYD88(L265P) occurs mainly in patients with mutated IGHV or chromosome 13q deletions and both alterations are associated with a superior survival.