Page 1070 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 953

however, the monosomy does not appear to confer an additional poor into clinically evident cancers. Perturbation of this immune response
prognosis beyond that of the complex karyotype. 201 presumably allows the persistence and propagation of abnormal
clones in MDS, but the extent to which this is pathogenically impor-
tant is not clear. 217
Other Karyotypic Abnormalities Several aspects of innate immunity have been shown to be abnormal
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in MDS patients. Some toll-like receptors, including TLR4, are
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A number of other cytogenetic abnormalities have been repeatedly overexpressed on MDS progenitor cells, and increased TLR signaling
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described in MDS, including –Y, del(13q), del(11q), del(12p) has been associated with higher degrees of apoptosis and the develop-
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or t(12p), del(9q), idic(X)(q13), t(11;16)(q23;p13.3), t(3;21) ment of cytopenias. In patients with del(5q), loss of miRs 145 and 146a
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(q26.2;q22.1), t(1;3)(p36.3;q21), t(2;11)(p21;q23), inv(3) from the common deleted region has been shown to upregulate tumor
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(q21q26.2) and t(6;9)(p23;q34). Most of these do not have spe- necrosis factor (TNF) receptor–associated factor 6, a TLR adaptor
cific phenotypes or associated with them, but some do confer prognostic E3 ubiquitin ligase, as well as Toll IL-1 receptor domain-containing
information and are included in the IPSS-R. In particular, –Y and adaptor protein (TIRAP), two important downstream effectors of
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del(11q) are designated “very good” prognosis; del(12p), del(20q), TLR4. del(5q) may also lead to the upregulation of CD14 on granu-
isolated del(5q), and normal karyotypes are considered “good’ ” trisomy locytes via heterozygous loss of mDia1, a scaffolding protein involved
8, del(7q), isochrome 17(q), trisomy 19, and trisomy 21 are considered in actin polymerization, which appears to confer abnormalities of the
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“intermediate;” monosomy 7, double deleted (7q), derivative (3q), and innate immune response. More recently, myeloid-derived suppressor
complex karyotype with exactly three abnormalities are considered cells have been shown to be significantly expanded in some patients
“poor,” and complex karyotypes with more than three abnormalities with MDS, and increased signaling in these cells via interaction with
are considered “very poor.” In addition, finding any of these in the S100A9, an important inflammatory mediator, has been shown to
appropriate clinical context, regardless of whether they are known to similarly stimulate inappropriate apoptosis in hematopoietic precursor
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carry prognostic information, is typically enough to warrant a diagnosis cells. Coincident with these findings, population-level data have
of MDS, even in the absence of clear morphologic dysplasia. suggested that patients with chronic inflammatory stimulation appear
to be at increased risk of developing MDS and AML. 223
Abnormalities in the adaptive immune system also exist in MDS.
The Microenvironment in Myelodysplastic Syndrome These have been particularly well described in hypoplastic variants,
which have similarities to aplastic anemia at both the cellular and
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The malignant transformation of hematopoietic progenitors in MDS genetic level, and both can respond to immune suppression. More
occurs not in isolation, but within the rich microenvironment of the broadly, oligoclonal T-cell receptor gene rearrangements can be found
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bone marrow stroma, which has come to be known as the “hemato- in MDS patients of all subtypes, and clinically detectable abnor-
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poietic niche.” Evidence has shown that under normal circum- malities of NK-cell, B-cell, and T-cell number and function can be
stances, hematopoiesis is in part regulated by paracrine signals released detected in a subset of patients as well. 226–228
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from nonhematopoietic mesenchymal cells, and evolving data
suggest that some of these processes are dysregulated in MDS. Early
circumstantial clues came from findings that patients with MDS and Abnormal Apoptosis
other hematologic malignancies have abnormal circulating levels of
cytokines known to affect hematopoiesis, including monocyte-colony Although MDS is typically characterized by normal or increased
stimulating factor, interleukin (IL) 1a, and granulocyte-monocyte marrow cellularity, abnormalities of apoptosis are frequently described,
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colony stimulating factor (GM-CSF), and other studies have particularly in low-risk variants, where increased apoptosis has been
shown that hematopoietic cells from MDS patients respond abnor- hypothesized to contribute to the development of ineffective hema-
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mally to these cytokines compared to cells from healthy controls. topoiesis. There are two major mammalian apoptosis pathways.
More recent studies have shown that hematopoietic progenitor cells The death receptor pathway, also known as the external pathway, is
transplanted into older mice display a narrower range of clonal expan- triggered by ligation of TNF family members, which leads to the
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sion than identical cells transplanted into younger mice, suggesting recruitment and activation of caspases at the cell surface. There is
that an aging niche might exert selective pressure on dominant ample evidence of abnormalities in this pathway in MDS; for
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hematopoietic progenitor cell clones. Furthermore, it has been instance, TNF-α levels have been shown to be increased in all MDS
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discovered that conditional deletion of the gene encoding dicer1, a subtypes, and other proapoptotic cytokines, including IL-8, trans-
microRNA processing enzyme, in osteoprogenitor cells can induce forming growth factor β, interferon-γ, and Fas ligand, have been
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myelodysplasia and secondary AML in mice; concurrently, other shown to be elevated as well. The other major apoptotic pathway,
studies have shown altered expression of DICER and DROSHA, known as the BCL-2 or intrinsic pathway, involves a complex balance
another microRNA-processing enzyme, in mesenchymal cells of between proapoptotic (BAX, BAK, BAD, PUMA, and others) and
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MDS patients. Even more intriguing, it has recently been shown antiapoptotic molecules (BCL-2, BCL-XL, MCL-1, and others),
that introduction of an activating B-catenin mutation in mouse and has also been shown to be abnormal in MDS. For example, ratios
osteoblasts can induce the development of AML through induction of proapoptotic (Bax/Bad) to antiapoptotic (Bcl-2/Bcl-XL) molecules
of the Notch ligand jagged1, which leads to Notch activation in are elevated in patients with lower-risk subtypes of MDS (RA and
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HSCs. As tantalizing as these findings are, the extent of their RARS), but the ratio reverses in RAEB and secondary AML, primar-
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pervasiveness across all MDS patients, and how microenvironmental ily driven by increased BCL-2 expression. Coordinate with this
alterations interact with the well-validated recurrent mutations found observation, but somewhat paradoxically, inhibition of apoptosis by
in hematopoietic cells, has yet to be determined. It is worth noting BCL-2 appears to prevent leukemic transformation in murine models
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that HSC transplantation, which involves only the transplantation of of MDS. Preclinical studies further suggest that inhibition of
hematopoietic elements and not stroma, can be curative for some BCL-2 and other antiapoptotic molecules may delay progression of
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patients with MDS, implying that at least in these patients, the niche disease and may sensitize MDS cells to hypomethylating agents
is not sufficient to sustain disease. such as azacitidine, but clinical trials combining these approaches
have not yet been performed. 237
Immune Dysregulation
Transformation to Acute Leukemia
In normal human tissues, both the innate and adaptive immune
systems play important roles in identifying, isolating, and destroying Although MDS and AML are often uttered in the same breath and
early clones with malignant potential before they are able to transform conceptualized as two facets of a similar disease process, this is an