Page 1737 - Williams Hematology ( PDFDrive )

1712 Part XI: Malignant Lymphoid Diseases Chapter 105: Plasma Cell Neoplasms: General Considerations 1713

D, MMSET and c-MAF, MAFB. In addition, amplification of chromo- GENETIC ABNORMALITIES IN WALDENSTRÖM
some 1q and deletions to chromosomes 13q and 17p are commonly seen MACROGLOBULINEMIA
within myeloma patients. With regards to deletion of chromosome
86
17p, the number of patients presenting with this abnormality increases Alterations in one of myeloid differentiation primary response gene
as the disease progresses. 85,96 To accommodate the variability in cytoge- MYD88 have been identified in 90 percent of patients with macro-
107
netic markers, researchers have developed diagnostic criteria to aid in globulinemia. MYD88 is an adaptor protein important in TLR and
the management of patients with a variety of cytogenetic abnormalities IL-1 receptor (IL-1R) signaling pathways. MYD88 is recruited to the
with prognostic value and will be discussed below. activated receptor complex as a homodimer that complexes with the
IL-1R–associated kinase (IRAK) 4 to activate IRAK 1. It leads to NF-κB
activation via IκB α phosphorylation. Cell survival is enhanced by
CYTOGENETIC ABNORMALITIES AS MYD88 overexpression, which leads to Bruton tyrosine kinase (BTK)
PROGNOSTIC MARKERS IN PLASMA CELL phosphorylation. Combined use of IRAK and BTK inhibitors results in
NEOPLASM synergistic killing of MYD88-expressing macroglobulinemia cells. High
rates of response have been observed in a clinical trial with a BTK inhib-
One model has become the standard for myeloma prognostic risk itor in relapsed and refractory patients. 108
assessment: The Mayo stratification of myeloma and risk-adapted ther-
apy (mSMART). 99,100 Historically, risk assessment was categorized into
two groups, standard or high-risk. The mSMART guidelines add an THE MARROW MICROENVIRONMENT
intermediate-risk subgroup to better assess the appropriate treatment
regimen. The standard-risk group consists of patients presenting with The marrow microenvironment, discussed in detail in Chap. 5, provides
either the t(6;14) or t(11;14) translocation as well as the hyperdiploid a highly supportive tumor microenvironment (TME) for the develop-
group, whereas the intermediate-risk group comprises patients present- ment, growth, and survival of neoplastic cells in patients with myeloma.
ing with the t(4;14) translocation and deletions of chromosome 13 or In the great majority of cases, the clonal expansion of these cells in the
hypodiploidy; the high-risk group is made up of patients presenting marrow is associated with increased blood vessel formation (neoangio-
with the t(14;16), the t(14;20), or deletion 17p13. Patients with dele- genesis) and, more importantly, myeloma bone disease (MBD).
tion of chromosome 13 by metaphase cytogenetics (not by FISH) are Nonmalignant stromal cells in the marrow secrete cytokines and
also considered high risk. The mSMART guidelines do not take into chemokines that promote myeloma cell growth and survival upon bind-
account all cytogenetic abnormalities seen in myeloma samples. There ing to specific receptors on the myeloma cell surface. Tumor promoters
has been considerable research performed to identify prognostic mark- include IL-6, insulin-like growth factor 1 (IGF-1), VEGF, B-cell activat-
ers within patients, including mRNAs and cell-surface receptors such as ing factor (BAFF), fibroblast growth factors (FGFs), stroma cell-derived
CD20+ samples as a prognostic marker. Chromosome 1 changes are factor 1α (SDF-1α, a.k.a. C-X-C motif chemokine 12 or CXCL12), and
101
important markers in myeloma; patients harboring the 1p deletion have tumor necrosis factor α (TNF-α). Direct physical interaction of mye-
a poor outcome. The amplification of chromosome 1q has also been loma and marrow stromal cells by virtue of cell-to-cell adhesion may
102
identified as an important locus in myeloma. Amplification of 1q21 is further enhance the cellular signaling pathways that are activated by
a poor prognosis marker in PCN and the frequency of 1q21 amplifica- cytokines and chemokines, thereby facilitating migration of myeloma
tions increases as the disease progresses. Furthermore, studies have cells to distant marrow and/or extramedullary sites (tumor dissem-
30
identified the chromosome 1q genes, NEK2 and CKS1B, as markers of ination). Myeloma-to-bone mesenchymal stem cell adhesion is also
aggressive disease and poor prognosis. 92,103 Presently, alterations to chromo- involved in the acquisition of drug resistance by tumor cells, underlying
some 1 are the only chromosomal markers not incorporated into the com- tumor relapse and/or refractory disease in patients with myeloma. 109
monly accepted prognostic models.
HOMING AND ADHESION OF MYELOMA CELLS
GENETIC ABNORMALITIES IN Homing and adhesion of myeloma cells to the marrow microenviron-
IMMUNOGLOBULIN LIGHT-CHAIN ment involves the CXCL12/CXCR4 pathway and a number of homo- or
AMYLOIDOSIS heterotypic adhesion factors, including CD44 (an anionic, nonsulfated
glycosaminoglycan called hyaluronan), very-late antigen 4 (VLA-4,
The clonal plasma cell burden in AL is usually small and similar to that composed of integrins α [CD49d] and β [CD29]) and its receptor, vas-
1
4
seen in patients with monoclonal gammopathy. Because the prolifer- cular cell adhesion molecule 1 (VCAM-1, CD106), leukocyte function–
ation rate of plasma cells is very low, chromosomal aberrations need associated antigen 1 (LFA-1, CD11a), neuronal cell–adhesion molecule
to be assessed by FISH analysis and not by conventional metaphase (NCAM, CD56), intercellular adhesion molecule 1 (ICAM-1, CD54),
cytogenetics. Approximately 70 percent of patients with AL have FISH and, importantly, syndecan 1 (CD138). Syndecan 1 is a transmembrane
abnormalities, the most common being IgH translocations (48 percent), heparan sulfate–containing proteoglycan that is usually expressed at
including t(11;14) and t(14;16). Other chromosomal abnormalities high levels on the myeloma cell surface. Syndecan 1-mediated adhesion
seen in AL include deletion 13/13q− and hyperdiploidy. The t(11;14) of myeloma cells promotes adhesion-dependent drug resistance and
104
occurs more frequently in AL (39 percent) than in monoclonal gam- bone resorption via expression of matrix metalloproteinases, among
mopathy or myeloma. Although cases with t(4;14) abnormality have other mechanisms.
105
been reported, those are exceptional and deletion 17p13 is not seen in Adhesion of myeloma cells to mesenchymal cells activates pleiot-
this form of amyloidosis. FISH analysis is important in this disease, ropic cellular signal transduction pathways that mediate the prolifera-
because t(11;14) is associated with an inferior prognosis in amyloidosis tive and survival-enhancing response of myeloma cells upon interaction
in contrast to myeloma, where it is associated with a good prognosis. In with the marrow microenvironment. Resistance of myeloma cells
another large study assessing the prognostic significance of cytogenetic to cytotoxic drugs is also promoted. These pathways include NF-κB
abnormalities, t(11;14) was not associated with an inferior outcome, but (nuclear factor kappa light-chain enhancer of activated B cells); PI3K/
gain of chromosome 1q21 clearly was. 106 AKT (phosphatidylinositol 3-kinase/protein kinase B/AKT oncogene),

Kaushansky_chapter 105_p1707-1720.indd 1712 9/18/15 9:45 AM