Page 1069 - Hematology_ Basic Principles and Practice ( PDFDrive )

952 Part VII Hematologic Malignancies

inversions are less common. Several of the most common karyotypic
abnormalities have been shown to have prognostic value, and one, Trisomy 8
del(5q), has enough unique biologic features to be its own subclas-
sification within the WHO criteria. Trisomy 8 is present in about 5% of MDS patients and can be found
in a wide range of other myeloid disorders, including AML, MPNs,
and aplastic anemia. In MDS, it can often be seen as a late, subclonal
del(5q) event. Although its contribution to pathogenesis is incompletely
187
understood, MDS patients with trisomy 8 appear to upregulate WT1,
Interstitial deletion of the long arm of chromosome 5 [del(5q)] is the an oncogene that can be mutated in AML (but very rarely in MDS),
42
most common chromosomal abnormality in MDS, and del(5q) is which may behave as a neoantigen that stimulates the expansion of
+
+
170
188
the only karyotypically-defined subtype recognized by the WHO. oligoclonal CD4 and CD8 T cells. Some evidence suggests that
Although the specific region affected varies between patients, there these populations may contribute to impairment of hematopoiesis in
189
are two commonly deleted regions (CDRs), one on 5q31.1 and the MDS patients with trisomy 8, which may explain why some patients
other at 5q32-33.3, with most patients having a deletion that includes with isolated trisomy 8 can have substantial responses to immune
190
171
both CDRs. MDS patients in whom del(5q) is the sole karyotypic suppression with antithymocyte globulin (ATG). Trisomy 8 has also
abnormality often display the “5q-minus syndrome,” which is clini- been associated with the development of paraneoplastic autoimmune
191
cally characterized by anemia, normal or elevated platelet count, phenomena, such as Behçet disease, again reflective of the immune
172
female predominance, lower risk of transformation to AML, and dysregulation characteristic of this cytogenetic abnormality.
a striking response to lenalidomide. 173
Our understanding of the pathobiology underlying del(5q) MDS
has improved substantially over the past several years; a key observa- del(20q)
tion was the lack of recurrent point mutations in genes located on
5q in other patients with MDS, which, coupled with the fact that del(20q) is an infrequent chromosomal aberration in MDS, occurring
192
most patients with del(5q) retain one normal chromosome 5, sug- in about 2% of patients. Patients with del(20q) frequently have
gested that the pathobiology could be best explained by haploinsuf- prominent thrombocytopenia, may have concomitant mutations of
174
193
ficiency of deleted genes. Indeed, it now appears that different U2AF1, and appear to have an intermediate prognosis, although
genes lost in the CDRs are responsible for different aspects of the 20q loss can also be a late event that indicates clonal progression of
194
5q− phenotype. For instance, haploinsufficiency of RPS14, a ribo- disease. The best candidate driver gene lying within the common
195
somal subunit gene located at 5q31.2, leads to p53 activation in deleted region is a tumor suppressor gene known as MYBL2, but
erythroid progenitors and is responsible for the dyserythropoiesis seen recent studies suggest that in myeloid models, a reduction in MYBL2
175
in the syndrome, and deletion of a key microRNA, miR-145, is levels below what would be predicted for classic haploinsufficiency is
176
196
responsible for the megakaryocytic component of the phenotype. required to drive clonal expansion. Although ASXL1 resides on
197
Separately, haploinsufficiency of CSNK1A1, which is located at 5q32 20q, it sits outside the CDR, and most patients with 20q abnor-
and encodes casein kinase 1-alpha, is responsible for the sensitivity malities do not have concomitant ASXL1 mutations.
to lenalidomide, which accelerates the ubiquitination and degrada-
tion of remaining casein kinase 1-alpha through a cereblon-dependent
177
process. Other studies have suggested that additional genes on 5q, 17p Deletions
179
178
181
180
including EGR1, APC , HSPA9 , NPM1 , and others may
contribute to features of the disease via a similar mechanism of Chromosome 17 abnormalities occur most often in MDS in associa-
haploinsufficiency in select cases. tion with complex karyotypes, which is most likely related to the fact
147
These points apply only to del(5q) as a sole karyotypic abnormal- that TP53 resides within the common deleted region on 17p. In
ity in MDS. When del(5q) is found with other chromosomal MDS, many patients with loss of 17p will have an inactivating
abnormalities, especially in the context of a complex karyotype (three mutation of their remaining copy of TP53, implying that haploinsuf-
198
or more karyotypic abnormalities, a finding often associated with ficiency is not in and of itself enough to drive pathogenesis. At the
TP53 mutations or 17p loss), the prognosis is poor and the response same time, patients almost never lose both copies of 17p as part of a
149
to lenalidomide seen in 5q− syndrome usually does not exist. larger chromosomal event, suggesting that some other gene or genes
Cooccurrence of del(5q) with TP53 mutation or 17p loss, in fact, in this region may be essential for hematopoietic cell survival. As with
occurs more frequently than would be expected by chance, suggesting TP53 point mutations, loss of 17p is an exceedingly poor prognostic
53
cooperativity of the two abnormalities. Del(5q) seen in the context factor in MDS, is frequently seen in cases of therapy-related disease,
of AML, even if the sole karyotypic abnormality, is a universally poor and often presages the development of treatment-refractory AML. 199
prognostic sign. 182
Complex and Monosomal Karyotypes
Chromosome 7 Abnormalities
Complex karyotypes, meaning those with three or more cytogenetic
169
Deletion of one entire copy of chromosome 7 (i.e., monosomy 7) abnormalities, are one of the more common abnormalities in MDS.
183
is also characteristic of MDS and portends a poor prognosis. The About half are associated with TP53 mutations; conversely, many, but
147
pathogenesis of chromosome 7 abnormalities is incompletely under- not all, patients with TP53 mutations have complex karyotypes. As
stood. Several genes recurrently mutated in MDS, including opposed to 17p abnormalities, which are reflective of the TP53 loss
184
123
124
EZH2, MLL3, and CUX1, lie on 7q, and it has been hypoth- itself, complex karyotypes are instead downstream effects of p53 loss
esized that loss of some or all of chromosome 7 contributes to MDS and represent the type of structural DNA damage that would have
pathogenesis via a haploinsufficiency mechanism similar to that seen triggered p53-mediated apoptosis in normal cells. The exceedingly
in del(5q). If such a mechanism exists, however, the evidence sup- poor prognosis associated with complex karyotypes is in fact probably
porting it has not yet been produced. Part of the difficulty in a proxy for p53 loss; the half of patients with complex karyotypes who
proving its existence lies in the fact that unlike del(5q), there is no have intact p53 function appear to have prognoses similar to patients
common deleted region on chromosome 7 in which to focus efforts with normal cytogenetics. Monosomal karyotypes, defined as complete
185
at driver gene discovery. It is important to note that in the revised loss of at least two entire chromosomes or one monosomy plus one
IPSS (IPSS-R), del(7q) is considered to be an intermediate-prognosis other abnormality, are also common and also tend to confer a poor
abnormality distinct from monosomy 7, which is classified as poor prognosis, particularly when associated with monosomy 7 or mono-
200
prognosis. 186 somy 5. When monosomal and complex karyotypes occur together,