Page 1812 - Williams Hematology ( PDFDrive )

1786 Part XI: Malignant Lymphoid Diseases Chapter 109: Macroglobulinemia 1787

polymerase chain reaction (PCR) assays. 35–40 MYD88 L265P is expressed in CXCR4 WHIM Mutations
90 to 95 percent of WM cases when more sensitive allele-specific PCR has The second most common somatic mutation after MYD88 L265P revealed
been employed, using both CD19-sorted and unsorted marrow cells. 36–40 by WGS was found in the C-terminus of the CXCR4 receptor. These
By comparison, MYD88 L265P was absent in myeloma samples, including mutations are present in 30 to 35 percent of WM patients, and impact
IgM myeloma, and was expressed in a small subset (6 to 10 percent) of serine phosphorylation sites that regulate CXCR4 signaling by its only
marginal zone lymphoma patients, who surprisingly have WM-related known ligand, stromal cell-derived factor (SDF)-1a (CXCL12). 29,50–52
features. 36–38,41 By PCR assays, 50 to 80 percent of IgM MGUS patients, The location of somatic mutations found in the C-terminus of CXCR4
also express MYD88 L265P , and expression of this mutation was associ- in WM are similar to those observed in the germline of patients with
ated with increased risk for malignant progression. 36–38,42 The presence WHIM (warts, hypogammaglobulinemia, infections, and myelo-
of MYD88 L265P in IgM MGUS patient suggests a role for this mutation kathexis) syndrome, a congenital immunodeficiency disorder char-
as an early oncogenic driver, and other mutations and/or copy number acterized by chronic noncyclic neutropenia. Patients with WHIM
53
alterations leading to abnormal gene expression are likely to promote syndrome exhibit impaired CXCR4 receptor internalization following
disease progression. 29 SDF-1a stimulation, which results in persistent CXCR4 activation and
The impact of MYD88 L265P to growth and survival signaling in myelokathexis. 54
WM cells has been addressed in several studies (Fig. 109–2). Knock- In WM patients, two classes of CXCR4 mutations occur in the
down of MYD88 decreased survival of MYD88 L265P -expressing WM C-terminus. These include nonsense (CXCR4 WHIM/NS ) mutations,
cells, whereas survival was enhanced by knock-in of MYD88 L265P versus which truncate the distal 15- to 20-amino-acid region, and frameshift
43
wild-type MYD88. The discovery of a mutation in MYD88 is signifi- (CXCR4 WHIM/FS ) mutations, which compromise a region of up to 40
cant given its role as an adaptor molecule in toll-like receptor (TLR) amino acids in the C-terminal domain. 29,50 Nonsense and frameshift
44
and interleukin-1 receptor (IL-1R) signaling. All TLRs except for mutations are almost equally divided among WM patients with CXCR4
TLR3 use MYD88 to facilitate their signaling. Following TLR or IL-1R somatic mutations, and more than 30 different types of CXCR4 WHIM
stimulation, MYD88 is recruited to the activated receptor complex as mutations have been identified in WM patients. 29,50 Preclinical stud-
a homodimer which then complexes with IRAK4 and activates IRAK1 ies with WM cells engineered to express nonsense and frameshift
and IRAK2. 45–47 Tumor necrosis factor receptor–associated factor 6 is CXCR4 WHIM -mutated receptors have shown enhanced and sustained
then activated by IRAK1 leading to NFκB activation via IκBα phospho- AKT and extracellular signal-regulated kinase (ERK) signaling follow-
48
rylation. Use of inhibitors of MYD88 pathway led to decreased IRAK1 ing SDF-1a relative to CXCR4 (see Fig. 109–2), as well increased cell
WT
and IκBα phosphorylation, as well as survival of MYD88 L265P expressing migration, adhesion, growth and survival, and drug resistance of WM
WM cells. These observations are of particular relevance to WM since cells. 51,55,56
49
NFκB signaling is important for WM growth and survival. Bruton
tyrosine kinase (BTK) is also activated by MYD88 L265P 43 Other Somatic Events
. Activated BTK
coimmunoprecipitates with MYD88 that could be abrogated by use of a Many copy number alterations have been revealed in WM patients that
BTK kinase inhibitor, and overexpression of MYD88 L265P , but not wild- impact growth and survival pathways. Frequent loss of HIVEP2 (80 per-
type(WT) MYD88, triggers BTK activation. Knockdown of MYD88 by cent) and TNFAIP3 (50 percent) genes that are negative regulators of
lentiviral transfection or use of a MYD88 homodimerization inhibitor NFkB expression (Fig. 109–2), as well as LYN (70 percent) and IBTK
also abrogated BTK activation in MYD88 L265P -mutated WM cells. (40 percent) that modulate B-cell receptor (BCR) signaling have been

Figure 109–2. MYD88 L265P and CXCR4 WHIM
mutations are highly prevalent in patients
TLR 4 IL R CXCR 4 with Waldenström macroglobulinemia, and
1
trigger transcriptional factors that include
nuclear factor κB (NFκB), AKT, and extra-
cellular signal-regulated kinase (ERK) that
support the growth and survival of lymp-
TIRAP hoplasmacytic cells.

L265P L265P
BTK MYD88 MYD88 PI Kc
P IRAK 4 P P IRAK 4 3

P IRAK 1 IRAK 1
P P Nonsense and frameshift
TAK 1 TRAF6
CXCR4 WHIM mutations
AKT
P
P NEMO MEK
IKK` IKKa P P P
IkB` P ERK
P
p50 p65
TNFAIP 3
HIVEP 2 P NFkB Survival

Kaushansky_chapter 109_p1785-1802.indd 1787 9/21/15 12:30 PM