The frequency of clonal karyotype anomalies varies considerably between the different BCR/ABL
-negative CMPD entities. The presence of karyotype abnormalities at diagnosis per se seems to be prognostically negative [9
]. CIMF has the highest karyotype aberration rate with 33–43% of all cases, followed by PV in 33–35%, whereas in ET, clonal abnormalities are extremely rare (<5%) [22
]. In CMPD-U, aberrant karyotypes were reported in ~20% [22
], but definition of the true incidence is difficult due to the heterogeneity of subtypes in this category.
Chromosomal changes in the CMPD are not specific, but their presence at least confirms the diagnosis of a malignant hematopoietic disorder and contributes additional aspects to differential diagnosis. This can be exemplified in the 9p-aberrations which are closely associated to PV and to CIMF. In addition, translocations involving ABL, PDGFRA, PDGFRB or other tyrosine kinases can be detected by chromosome banding analyses, allowing the identification of patients who probably benefit from treatment with tyrosine kinase inhibitors.
Thus, chromosome banding analyses contribute a lot at diagnosis in many in cases with a suspicious or proven CMPD. However, they do not lead to important information for clinically clearly proven cases of ET. Cytogenetics may also be needed for the follow-up of the CMPD, as leukemic transformation is characterized in many cases by clonal evolution to more complex karyotypes resulting in higher rates of chromosomal abnormalities of ≥90% [9
Interphase (IP-), metaphase (HMF-), and 24-color fluorescence in situ hybridization (FISH) may further confirm and clarify the results of the chromosome banding analyses. IP-FISH probes can be used for future MRD studies. Nearly all typically observed aberrations—e.g., +8, +9, gain of 9p, or del(20q)—can be monitored.
Trisomy 8 is the most frequent aberration in the CMPD being detected in ~20% of all cytogenetic aberrant PV cases and in ~10% in chromosomally aberrant CIMF—mostly as sole abnormality or in combination with +9. This is followed by trisomy 9 in ~10% of all cytogenetically aberrant cases. Partial trisomies of 9p are equally frequent with a special association to PV [27
]. Other recurrent aberrations are deletions of 13q and 20q and partial trisomies of 1q [9
], whereas +19, +21, −7, −Y, del(12p), and i(17q) are less frequent.
Chromosomal changes show a characteristic distribution within the diverse CMPD. In detail, PV shows, as the most frequent changes, +9, followed by +8 and by del(20q) [23
]. CIMF has a more heterogeneous pattern with deletions of 13q and of 20q both in ~9% of all cases [9
], structural abnormalities of 1q and 5q, and chromosome 7 abnormalities [23
]. In ET, chromosomal abnormalities are found in <5% of cases only, mostly represented by numerical gain of chromosome 9. Table presents an overview on recurrent cytogenetic and molecular markers in the CMPD.
Balanced translocations as revealed by cytogenetics are rare in the CMPD. Many of these lead to the disruption of genes encoding tyrosine kinases. The breakpoints cluster in two regions at 5q31-33 and 8p11 which target the platelet-derived growth factor receptor beta [e.g., in the t(5;12)(q31q33;p12)/ETV6-PDGFRB
)] and the fibroblast growth factor receptor 1 kinase [e.g., in t(8;13)(p11;q12)/FGFR1-ZNF198
)]. Further, the ABL
non-receptor tyrosine kinase might be involved in these rare rearrangements as in the t(9;12)(q34;p13)/ETV6-ABL
]. The 8p11 myeloproliferative syndrome shows a specific profile outlined by frequent association to Non-Hodgkin’s lymphoma, high leukemic transformation rates, eosinophilia, and CML-like findings in bone marrow cytomorphology. It is most frequently caused by the t(8;13)(p11;q12)/FGFR1-ZNF198
, but many other variants all involving 8p11/FGFR1
have been described. Bone marrow cytomorphology shows CML-like findings and eosinophilia [12
]. As patients with PDFRB
rearrangements are all candidates for tyrosine kinase inhibitor treatment, detection of these rare rearrangements by cytogenetics in combination with FISH and PCR is obligatory. For an overview on these reciprocal gene fusions, we refer to Cross and Reiter [32