Page 1594 - Hematology_ Basic Principles and Practice ( PDFDrive )

1420 Part VII Hematologic Malignancies

MUTATION IN MYD88

A highly recurrent somatic mutation (MYD88 L265P ) was first identi-
fied in patients with WM by whole genome sequencing (WGS) and
confirmed by multiple studies through Sanger sequencing and/or
allele-specific polymerase chain reaction (PCR) assays. 35–40 MYD88 L265P
is expressed in 90% to 95% of WM cases when more sensitive
allele-specific PCR is employed using both CD19-sorted and unsorted
BM cells. 36–40 By comparison, MYD88 L265P was absent in myeloma
samples, including IgM myeloma, and was expressed in a small subset
(6% to 10%) of patients with marginal zone lymphoma, who surpris-
ingly have WM-related features. 36–38,41 By PCR assays, 50% to 80%
of patients with IgM MGUS also express MYD88 L265P , and expression
of this mutation was associated with increased risk for malignant
progression. 36–38,42 The presence of MYD88 L265P in patients with IgM
MGUS suggests a role for this mutation as an early oncogenic driver,
and other mutations and/or copy number alterations leading
to abnormal gene expression are likely to promote disease
Fig. 87.1 MARROW FILM FROM A PATIENT WITH WALDEN- progression. 29
STRÖM MACROGLOBULINEMIA. Note infiltrate of mature lympho- The impact of MYD88 L265P to growth and survival signaling in
cytes, lymphoplasmacytic cells, and plasma cells. (Used with permission from WM cells has been addressed in several studies (Fig. 87.2). Knockdown
Marvin J. Stone, MD.) L265P
of MYD88 decreased survival of MYD88 -expressing WM cells,
whereas survival was enhanced by knock-in of MYD88 L265P versus
43
wild-type (WT) MYD88. The discovery of a mutation in MYD88

TLR4 IL1R CXCR4

TIRAP
L265P L265P
BTK MYD88 MYD88 PI3Kδ
P IRAK4 P P IRAK4
IRAK1 NONSENSE AND FRAMESHIFT
IRAK1
P P CXCR4 WHIM MUTATIONS
P
TAK1 TRAF6
AKT
P
P NEMO MEK
IKKα IKKβ P P P

IKBα P
ERK
P
TNFAIP3 p 50 p 65
P
HIVEP2 NFkB SURVIVAL
Fig. 87.2 MYD88 L265P AND CXCR4 WHIM MUTATIONS ARE HIGHLY PREVALENT IN PATIENTS
WITH WALDENSTRÖM MACROGLOBULINEMIA AND TRIGGER TRANSCRIPTIONAL
FACTORS THAT INCLUDE NFκB, AKT, AND ERK THAT SUPPORT THE GROWTH AND SUR-
VIVAL OF LYMPHOPLASMACYTIC CELLS. BTK, Bruton’s tyrosine kinase; CXCR4, C-X-C chemokine
receptor type 4; ERK, Extracellular signal-regulated kinase; HIVEP2, human immunodeficiency virus type I
enhancer binding protein 2; IKBα, nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor α;
IKK, inhibitor of nuclear factor-κB kinase; IL1R, interleukin-1 receptor; IRAK, interleukin receptor-associated
kinase; MEK, mitogen-activated protein kinase kinase; NEMO, nuclear factor-κB essential modulator; NFκB,
nuclear factor-κB; PI3Kδ, phosphoinositide 3-kinase δ; TAK1, transforming growth factor β-activated kinase
1; TIRAP, Toll-interleukin 1 receptor domain-containing adaptor protein; TLR4, Toll-like receptor 4;
TNFAIP3, tumor necrosis factor α-induced protein 3; TRAF6, tumor necrosis factor α receptor-associated
factor 6; WHIM, warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.