Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes
Introduction
Already in the late 1950s and early 1960s, cytogenetic studies of acute myeloid leukemias (AMLs) revealed that many of them were aneuploid, often with hyperdiploid modal numbers at 47 or 48 [1], [2], [3]. Although it was not possible to characterize further the chromosomal abnormality patterns in this pre-banding era, one aberration seemed quite common, namely a “group C-trisomy” [4], [5]. When the various chromosome banding techniques were introduced in the 1970s, it was soon realized that the extra C chromosome in AML, as well as in myelodysplastic syndromes (MDS), in the vast majority of the cases represented a trisomy 8 [6], [7], [8]. To date, close to 500 AMLs and 400 MDS with this abnormality as the sole chromosomal anomaly have been published [9].
In spite of the quite substantial number of trisomy 8-positive cases reported, many issues regarding the epidemiology, etiology, morphologic, immunophenotypic, and prognostic features, association with other genetic abnormalities, cell of origin, and the pathogenetic impact of +8 still needs to be clarified, as will be illustrated in the present review of AML and MDS with trisomy 8 as the sole chromosomal change.
Section snippets
Epidemiology
A survey of cytogenetically abnormal AML and MDS cases reported in the literature [9] shows that trisomy 8 is present in 16–17% of these disorders and that it is the sole change in 6 and 11% of the AMLs and MDS, respectively (Table 1, Table 2); frequencies agreeing well with published series of karyotypically characterized AMLs and MDS [10], [11], [12], [13], [14]. In fact, +8 is, on the whole, the most common chromosomal change in AML and the second, next to monosomy 7, in MDS; as the sole
Etiology
Apart from the fact that trisomy 8 most likely arises through non-disjunction, little is known about the constitutional/environmental risk factors for this chromosome abnormality.
It is generally accepted that +8 in AML and MDS is an acquired abnormality, being present in the neoplastic cells only. However, trisomy 8 may also be constitutional, occurring as a mosaicism (CT8M) in approximately 0.1% of all recognized pregnancies [32]. Typically, CT8M is the consequence of a postzygotic
Morphologic, immunophenotypic, and prognostic features
Although +8 as the sole change may be found in all morphologic subgroups of AML, it has been reported that it is particularly frequent in M1, M2, M4, and M5, with a higher incidence in M5a than in M5b [12], [13], [29], [58], [59], [60], [61], [62], [63]. An updated database search [9] reveals that the frequencies of +8 as the sole change vary significantly among the different morphologic subtypes, being most common in M5, albeit with identical incidences in the M5a and M5b subgroups (Table 1).
Trisomy 8 associated with other chromosomal abnormalities
In AML, trisomy 8 also occurs in association with other abnormalities in 10% of the cytogenetically abnormal cases (Table 1). In fact, trisomy 8 is quite common as a secondary change to a large number of primary AML-associated translocations and inversions [81], being particularly prevalent in cases with t(7;12), t(9;11), and t(1;11) (Table 7). Furthermore, it is the most common secondary change in AMLs with t(9;11)(p21;q23), t(9;22)(q34;q11), t(11;19)(q23;p13), and t(15;17)(q22;q21), and the
Cell of origin
During the past decade, cancer stem cells, the existence of which was first proposed more than 40 years ago, have received much attention [92], [93], [94]. It is now generally accepted, or at least widely believed, that hematologic malignancies are sustained by leukemic stem cells, capable of both initiating and maintaining the disease. Apart from functional studies, FISH analyses of neoplasia-associated genetic abnormalities in morphologically or phenotypically defined cell populations have
Pathogenetic impact of trisomy 8
Although several attempts to elucidate the pathogenetic impact of +8 have been made, the functional and molecular genetic outcome of this abnormality remains elusive. Possible mechanisms that may be involved include global gene expression changes, resulting from the gene dosage effect generated by the trisomy, deregulation of imprinted loci, and duplication of rearranged or mutated genes present in the extra chromosome 8. The pros and cons of these various possibilities are reviewed below.
Trisomy 8 is not sufficient for leukemogenesis
Trisomy 8 is an important early event, but several lines of evidence quite strongly indicate that it is not sufficient for leukemogenesis. First, although individuals with CT8M have an increased risk of myeloid malignancies, only a minority develop AML or MDS, with a latency of several years [37], [39], [42]. Second, several cytogenetic as well as clonality studies of trisomy 8-positive MDS cases have indicated that +8 is not the primary event in the malignant transformation, i.e. also the
Acknowledgments
The original research on which this article is based was supported by the Swedish Cancer Society and the Swedish Children's Cancer Foundation. We are grateful to Dr. Thoas Fioretos, Dr. Fredrik Mertens, Dr. Nils Mandahl, and Dr. Felix Mitelman for helpful comments and suggestions.
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