Cytogenetics of Myelodysplastic Syndrome

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This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12071581

Myelodysplastic syndromes (MDS) are heterogeneous groups of clonal myeloid disorders characterized by unexplained persistent peripheral blood (PB) cytopenia(s) of one or more of the hematopoietic lineages, or bone marrow (BM) morphologic dysplasia in hematopoietic cells, recurrent genetic abnormalities, and an increased risk of progression to acute myeloid leukemia (AML). Cytogenetics has been an important and a necessary parameter in the diagnosis of MDS. The WHO relies heavily on cytogenetic aberrations in MDS. In addition to establishing a clonal process in patients with peripheral blood cytopenia, cytogenetics plays a major role in the prognostication, clinical-morphologic correlation, theragnostic strategies, and in predicting the likelihood of progression to AML. In contrast to other myeloid malignancies, in which the diagnosis is defined by a single cytogenetic event, there is a vast spectrum of cytogenetic-defining lesions in MDS, making diagnosis very challenging.

myelodysplastic syndromes cytogenetics comprehensive cytogenetic scoring system

1. Introduction

Cytogenetics has been an important and a necessary parameter in the diagnosis of Myelodysplastic syndromes (MDS). The WHO relies heavily on cytogenetic aberrations in MDS. In addition to establishing a clonal process in patients with peripheral blood cytopenia, cytogenetics plays a major role in the prognostication, clinical-morphologic correlation, theragnostic strategies, and in predicting the likelihood of progression to acute myeloid leukemia (AML). In contrast to other myeloid malignancies, in which the diagnosis is defined by a single cytogenetic event (such as chronic myeloid leukemia and acute promyelocytic leukemia), there is a vast spectrum of cytogenetic-defining lesions in MDS, making diagnosis very challenging. Nevertheless, roughly 50% of MDS has normal cytogenetics. The cases with borderline dysplasia and normal cytogenetics present with diagnostic challenges. Various combinations of chromosomal lesions contribute to the large spectrum of clinicopathologic features of MDS. According to the WHO, MDS may still be diagnosed in a patient with unexplained cytopenia, when all of the other secondary causes of refractory cytopenia are essentially and exhaustibly ruled out, and as long as there are MDS-defining cytogenetic abnormalities identified (with some exceptions) ^[1].

The results from cytogenetic studies, both by conventional karyotyping (G-banding) and fluorescence in situ hybridization (FISH) assays, serve as strong parameters included in the revised International Prognostic Scoring System (IPSS-R) score for MDS. As such, the IPSS-R has been proven to be beneficial for predicting the clinical outcomes for untreated MDS patients and aiding in the design of clinical trials for the disease ^[2]. The comprehensive cytogenetic scoring system (CCSS) was adapted by the WHO, which defines the specific prognostic stratification of MDS based on the existing cytogenetics clone. The IPSS-R encompass five cytogenetic subgroups, which gives more weight to chromosomal aberrations than the previous IPSS. The five cytogenetic risk groups were defined according to the new CCSS, that was based on a large multicenter database. Overall survival (OS) was reported to be significantly different independently from the cytogenetics’ status ^[3].

2. del(7q) or Monosomy 7

Monosomy 7 (-7) and deletions of the long arm of chromosome 7 (del(7q)) are found in several myeloid neoplasms, suggesting its crucial role in disease pathogenicity. They occur either in isolation or as part of a complex karyotype, and are generally associated with unfavorable prognosis in certain disease entities. In MDS, the isolated cytogenetic abnormality of del(7q) has been categorized in the intermediate prognostic subgroup, whereas isolated cytogenetic abnormality of -7 has been classified as belonging in the poor prognostic subgroup. Among the patients with del(7q), there was a tendency toward better survival compared with the patients with complete -7 as an isolated abnormality and as a noncomplex aberration. However, because the survival difference between these related cytogenetic lesions are not statistically significant, they are then regarded as a single cytogenetic category ^[4]. The chromosome 7 anomalies are reported in approximately 10% cases of de novo MDS, and up to 50% of therapy-related MDS ^[5].

The deletion breakpoints in chromosome 7 are heterogeneous and the deletions are often interstitial. The majority of the cases had proximal breakpoints in 7(q11) or 7(q22). The commonly deleted regions on 7q identified in MDS are located at positions 7q22, 7q32-33, and 7q35-36 ^[6]. Monosomy 7, occurring as the sole cytogenetic anomaly in a small but significant number of cases, may denote a dominant mechanism involving critical tumor suppressor gene(s) ^[7]. Previous studies identified possible driver genes contributing to the pathogenesis of -7/del(7q), including CUX1, EZH2, LUC7L2, MLL3, and SAMD9/9L ^[8]. However, specific therapies have not yet been developed.

CUX1 is a conserved, haplo-insufficient tumor suppressor frequently deleted in myeloid neoplasms. It encodes a homeodomain-containing transcription factor, which is located in chromosome band 7q22.1. In the RNA-sequencing data, a CUX1-associated cell cycle transcriptional gene signature was identified, suggesting that CUX1 exerts tumor suppressor activity by regulating the proliferative genes ^[9].

EZH2 acts as a tumor suppressor for myeloid malignancies. It is located at chromosome 7q36, which encodes a member of the polycomb group family, that forms multimeric protein complexes which are involved in maintaining the transcriptional repressive state of genes. It encodes a histone methyltransferase which functions in the epigenetic silencing of the genes involved in stem cell renewal ^[10]. However, deletions in 7q do not result in the loss of the EZH2 gene ^[11].

3. del(5q)

The 5q- syndrome was first reported in 1974 ^[12]. Currently, the only subtype of MDS defined by a genetic abnormality is the group with an isolated deletion in the long arm of chromosome 5 (del(5q)). This specific type of MDS belongs to the good prognostic subgroup. The most common symptom is usually of macrocytic anemia, with thrombocytosis a more common occurrence than thrombocytopenia ^[1].

The most common abnormality includes the interstitial deletion of the long arm of chromosome 5. Larger losses of the 5q arm, by deletion of the centromeric or telomeric regions or mutations involving the NPM1 or MAML1 and APC genes, have been related to a higher risk of MDS and an earlier risk of transformation to AML ^[13]^[14]. The MDS with isolated del(5q) are the most common genetic abnormality seen in de novo MDS and they have a relatively better prognosis and a reduced risk of transformation to AML ^[15]. However, this abnormality may be a part of complex cytogenetics, in which the prognosis of these cases is poorer. From these MDS cases, del(5q) is not necessarily a primary genetic event, and this may be acquired after other disease-initiating mutations, particularly the epigenetic modifier mutations ^[16].

It was discovered that the haploinsufficiency of several genes located in this region are capable of generating the clinical phenotype in patients with MDS. The loss of one RPS14 allele, for example, can recapitulate the dyserythropoiesis seen in MDS del(5q). The loss of this protein has been shown to upregulate p53, primarily in erythroblasts, and therefore to promote apoptosis from these cells. The mutations of p53 are significantly associated with the loss of del(5q) and a complex karyotype, and this has not been associated with del(7q) ^[17]. Mutations in RPS14 are also found in about 25% of the patients with Diamond–Blackfan Syndrome, which leads to haploinsufficiency of RPS14 ^[18]. The haploinsufficiency of several other genes of the commonly deleted region include HSP9, CTNNA1, and EGR1 ^[13]. On the other hand, the loss of one copy of the microRNA miR-145 and miR-146 leads to the presence of preserved or even increased levels of the platelet count observed in MDS patients, with isolated del(5q) ^[19]. The loss of these microRNAs leads to the upregulation of TRAF6, resulting in thrombocytosis, neutropenia, and megakaryocytic dysplasia ^[20].

Lenalidomide is a thalidomide analog, which shows a dramatic therapeutic effect in patients with low-risk MDS. Its response rate was significantly higher among those with interstitial deletion involving chromosome 5q ^[18]. It can also reduce the transfusion requirement and can reverse cytologic and cytogenetic abnormalities in MDS with del(5q) ^[21].

4. del(20q) and Loss of Y

The deletion of the long arm of chromosome 20 (del(20q)) is a recurrently identified cytogenetic abnormality in myeloid neoplasms, including myeloproliferative neoplasms (MPN), MDS/MPN, MDS, and AML. However, unlike del(5q), del(20q) is not recognized by the WHO as a unique entity in MDS. Del(20q), as an isolated cytogenetic abnormality, can be seen in the bone marrow specimens of patients without morphologic diagnostic features of any of the myeloid neoplasms, and this may also be seen in patients with non-myeloid malignancies or unexplained cytopenias. Therefore, the WHO emphasizes that the presence of isolated del(20q) is not considered to be definitive clonal evidence of MDS in patients with unexplained cytopenia, in the absence of morphologic evidence of MDS ^[1]. This may impose a diagnostic dilemma on several MDS cases. The diagnostic samples of patients with isolated del(20q) without mutations have a very low risk for progression to a myeloid neoplasm, and approximately one third of the patients with mutations ultimately progressed into a myeloid neoplasm ^[22].

MDS with isolated del(20q) are categorized in the good cytogenetic prognostic subgroup by the IPSS-R. The breakpoints of del(20q) are heterogeneous. The most frequently mutated genes identified include U2AF1, ASXL1, SF3B1, TP53, and SRSF2. In MDS, del(20q) may cause deletion of the ASXL1 gene, and ASXL1 alteration exerts a negative impact on MDS with del(5q). This has also been correlated with a lower platelet count and a poor response to azacytidine (AZA) ^[23]. The ASXL1 mutations are found in 11 to 21% of patients with MDS and are a predictor of poor OS ^[24]^[25]^[26]. The median survival of patients with del(20q) was 54 months, compared with 12 months in the patients with del(20q) plus other additional chromosomal abnormalities ^[27].

The deletion of the Y chromosome (-Y) belongs to the very good prognostic subgroup in MDS, as categorized by the IPSS-R, but has also been attributed to an age-related phenomenon. It is noteworthy that, although it has been associated with better prognosis in MDS, the exact mechanism remains unknown. It was also known that the loss of X in women and the loss of Y in men increases with age ^[28]. Deletion of the Y chromosome has been observed in about 4 to 10% of male patients as a single cytogenetic abnormality in MDS ^[3]. Although -Y influences the prognosis in MDS, it occurs in elderly men with no evidence of hematologic disease. It was evident that the CD34+ cells carrying -Y are more prevalent in male patients with MDS than the healthy counterparts ^[29].

5. Trisomy 8

Trisomy 8 (+8) is the most common chromosomal gain in MDS, and is seen in about 11% of de novo MDS with an abnormal karyotype ^[30]. It belongs to the intermediate prognostic subgroup categorized by the IPSS-R. Although it is a common cytogenetic abnormality, the presence of isolated +8 is not considered as presumptive evidence of MDS without the minimal dysplastic morphologic criteria. One of the main reasons is that +8 can be found as a constitutional mosaicism in healthy individuals ^[31]. Several reports indicate that the presence of +8 is constitutional in 15 to 20% of MDS and acute leukemia patients ^[32]. Another reason that the sole presence of +8 is not a MDS-defining event is that it is also seen as a clonal aberration in aplastic anemia, which may also be a close differential diagnosis of MDS, but disappears after immunosuppressive therapy ^[33]. Therefore, the presence of unequivocal morphologic dysplasia is required to discriminate hypoplastic MDS from aplastic anemia. It was also noted that MDS with +8 responds well to immunosuppressive therapy, with an up to 67% response rate ^[34].

6. del(11q) and del(12p)

MDS with isolated del(11q) is associated with a very good prognosis (similar to -Y) characterized by the IPSS-R. It is a rare cytogenetic abnormality, which is reported to occur in 0.7% in de novo and secondary AML and MDS ^[35]. The KMT2A gene (previously referred to as MLL or mixed lineage leukemia gene) is located at the 11q23 breakpoint. It was shown that del(11q) is heterogenous at the molecular level and may signify cryptic rearrangements involving chromosome 11 or the KMT2A gene. Unlike in AML with del(11q), which harbors the cryptic KMT2A rearrangements, it was reported that MDS with del(7q) lacks this cryptic rearrangement, and therefore may potentially explain the biological differences between AML and MDS with del(11q) ^[36].

Another gene located at chromosome 11q23 telomeric to the KMT2A gene is the CBL gene. Being a signal transduction gene, the mutations in the CBL gene constitute important pathogenic lesions associated with AML progression, due to the impaired degradation of the activated tyrosine kinase ^[37]^[38].

Deletion in the short arm of chromosome 12 is a rare event in MDS, and occurs in 0.6 to 5% of the cases at diagnosis ^[39]. This was categorized in the good prognostic subgroup in the IPSS-R with an OS of 76 months ^[2]. It usually occurs as a very small interstitial deletion between 12p12.2 and 12p13.1, affecting the ETV6/TEL gene ^[40]. However, the ETV6 deletion is seen to be higher in AML than in MDS ^[41].

7. del(9q)

The deletions in the long arm of chromosome 9 are more commonly seen in AML than in MDS or MPN. The IPSS-R categorizes del(9q) in the intermediate risk subgroup with a median OS of 32 months. The myeloid neoplasms with del(9q) were identified as having a high prevalence of TET2 mutations, and the association was more pronounced when TET2 was the sole abnormality, with a frequency of 45% ^[42]. Recent data showed that del(9q) was removed from the list of MDS-defining cytogenetic abnormalities, because of its association with t(8;21) and the frequent occurrence in AML with NPM1 and biallelic CEBPA mutations ^[43].

8. t(17p) or Isochromosome 17q

The presence of a chromosome 17 abnormality in MDS has been correlated with poor prognostic features and very low OS, except for isochromosome 17q (i(17q)), which is associated with the intermediate risk prognostic subgroup by the IPSS-R. The association between a poor prognosis and a chromosome 17 abnormality in patients has also been found in the context of a complex karyotype. This was also correlated with the loss of 17.13.1, which contains the genetic loci of the tumor suppressor gene p53 (TP53) ^[44]. The significance of this cytogenetic aberration has been valuable in MDS and AML with TP53 mutations, due to its favorable response to hypomethylating agents (HMA), particularly decitabine ^[45]. TP53 is the most commonly mutated gene in human cancer. It functions as a transcription factor for cell cycle arrest, DNA repair mechanisms, apoptosis induction, and cellular differentiation. In MDS, the TP53 mutation was significantly associated with del(5q) syndrome, with its diverse roles in cell cycle, DNA repair and apoptosis leading to chromosomal instability, and AML transformation ^[46]. The association of TP53 in the pathogenesis of MDS was also seen in the context of therapy-related MDS (t-MDS), as defined by the WHO’s classification in 2016, wherein an exposure to cytotoxic or radiation therapy for a previous unrelated malignancy or autoimmune disease was documented ^[1].

9. t(11;16)

The balanced translocation of chromosome 11 and 16 occurs in approximately 3% of the therapy-related MDS cases ^[1]. The KMT2A gene (previously known as the MLL gene) has been mapped in the 11q23 locus and this gene forms fusion transcripts with more than 70 translocation partner genes. The KMT2A gene translocation results in the formation of a chimeric protein in its amino-terminal and fused in the carboxy-terminal portion of the fusion partner gene ^[47]. On the other hand, the CBP gene encodes a transcriptional adaptor/coactivator protein in the 16p13 locus, and is involved in the regulation of the cell cycle ^[48]. It was postulated that one possible explanation for the leukemogenesis of t(11;16)-positive MDS is the loss of function in CBP to regulate the cell cycle by its structural alteration when fused with KMT2A ^[49]. The OS of adult patients with t(11;16) in one study was similar to adult patients with therapy-related myeloid neoplasms and complex karyotypes ^[49].

10. inv(3) or t(3;3)

MDS with inversion 3 (inv(3)) and balance translocation of chromosome 3 (t(3;3)) are observed in approximately 1% of the cases, and has been categorized in the poor prognostic subgroup ^[1]. Myeloid neoplasms with inv(3)/t(3;3) often present with anemia, and platelet counts which may be normal or increased ^[50]^[51]. The chromosomal aberration involves protooncogene EVI1 at 3q26.2.2 or the longer form MECOM and RPN1, resulting in ectopic and overexpression of EVI1, or MECOM or the RPN1/EVI1 fusion transcripts, with RPN1 acting as an enhancer of EVI1 expression ^[52]^[53]. EVI1 has been associated with several signaling pathways, leading to cell growth, cell differentiation impairment, and cell survival ^[54]. GATA2 was also implicated and was observed to be overexpressed in these cases, suggesting its role in the development of chromosome 3 rearrangements ^[53].

11. t(6;9)

The translocation of chromosome 6 and 9 (t(6;9)) is a rare occurrence in MDS, occurring in 1% of all of the MDS cases ^[1]. The translocation results in the formation of a chimeric fusion protein DEK/NUP214 in der(6). This cytogenetic event has been associated with a poor prognosis in myeloid neoplasms. This abnormality is predominantly occurring as a sole karyotypic aberration, but a subset has been associated with a complex karyotype ^[55]. In AML, there is a high occurrence of FLT3-ITD mutations in patients with t(6;9) ^[55]. It was suggested that MDS with t(6;9) does share some clinicopathologic features with AML with t(6;9), which include comparably low hemoglobin levels, the presence of multilineage dysplasia, and some mutational landscape, however, it was also suggested that MDS cases are prognostically not equivalent to AML ^[56].

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