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• W3040331102 abstract "Double minutes (dmin) chromosomes are frequently detected in solid tumours,1 whereas they are exceedingly rare in myeloid malignancies [<1% of acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)],2 where they have been associated with poor prognosis.3 Dmin are found as small, acentric, spherical chromatin particles in an extrachromosomal localisation, being associated in most haematological neoplasms with the amplification of the transcription factors MYC, or less commonly, Histone-lysine N-methyltransferase 2A (KMT2A).4, 5 Of note, morphological analysis of cases with dmin, disclose blasts characterised by the presence of intracytoplasmic nuclear fragments that have been named ‘micronuclei’. In addition, blasts usually exhibit large basophilic cytoplasm with increased azurophilic granulation, suggesting pseudo-Chediak-Higashi granules, Auer rods and faggot cells, and invariably strong positivity for myeloperoxidase staining (MPO) staining.3, 6, 7 Here, we describe two patients with dmin-associated MYC amplification and the presence of micronuclei, one at the time of MDS diagnosis and the other one at the evolution to AML from MDS. A review of all MDS cases with the same clinicopathological and cytogenetic features published to date was performed. A 79-year-old man was referred to our Department due to bicytopenia. Blood test revealed a haemoglobin (Hb) level of 100 g/l, white blood cell count (WBC) of 4·8 × 109/l and platelet count of 59 × 109/l. The bone marrow (BM) film displayed hypercellularity, dyserythropoiesis, dysgranulopoiesis and 15% of blasts with cytoplasmic nuclear-like particles in form of micronuclei Fig 1A, heavy azurophilic granulation, Auer rods and faggot cells. Blasts showed strong positivity for MPO. G-banding study showed one clone with a variable number of dmin and trisomy 6 that evolves and adds a trisomy 19 (47, XY, +6, 4 ~ 25dmin[6]/48,XY,idem, +19[2]/46, XY[12]) Fig 1C. Metaphase fluorescence in situ hybridisation (FISH) analysis with a MYC probe confirmed multiple signals on the dmin Fig 1D, whereas KMT2A probe did not. Of note, by superimposing FISH and cytological slide images, the MYC signals were not allocated in the micronuclei. The final diagnosis was MDS with excess blasts type-2 with complex karyotype and MYC amplification. The patient rapidly progressed to AML and died 3 months after the diagnosis. An 81-year-old man was diagnosed with MDS with multilineage dysplasia and normal karyotype. While receiving treatment with erythropoiesis-stimulating agents with haematological response, the patient presented with a rapid change in the blood counts after 4 months of treatment: Hb level of 100 g/l to 87 g/l, WBC of 5 × 109/l to 12 × 109/l and platelet count of 177 × 109/l to 130 × 109/l, at diagnosis and progression respectively). BM film showed severe dysplastic features in all the cell lines, 26% of large-sized blasts with micronuclei, increased azurophilic granules, Auer rods and faggot cells Figure 1B not present at MDS diagnosis. Karyogram revealed a variable number of dmin: 62,XY,+3 ~ 18dmin[19]/46,XY[1] and FISH analysis showed multiple MYC amplicons. Again, MYC amplifications were not located in the micronuclei. The diagnosis of AML with myelodysplasia-related changes was made. The patient received six cycles of hypomethylating agents with no response. The presence of dmin in haematological neoplasms is exceedingly rare, being AML the most frequent associated haemopathies (Mitelman et al., 2020). Dmin have also been described in MDS, although to the best of our knowledge only six cases have been reported to date (Table I).3, 8, 9 Of note, all cases published with MDS and AML with dmin share common clinicopathological and genetic characteristics. Thus, blasts from cases with dmin exhibit the presence of rounded, paired intracytoplasmic, medium-size, nuclear-like structures so-called micronuclei. It has been hypothesised that these micronuclei arise from the nucleus by budding during S phase or after mitosis, as the nuclear membrane adjusts and contains damaged chromosomes.10 In order to rule out that the micronuclei contain part of the MYC amplifications, we performed a FISH analysis using the MYC probe in blast cells where the micronuclei where present. Of note, we found multiple small signals that did not match with the micronuclei Fig 1D, therefore, excluding the physical relationship between the cytological and genetic features observed in both cases. MYC 3 RAEB-1 1 CMML MYC in 2 MYC and KMT2A negative in 1 Remarkably, in both of our patients Auer rods and faggot cells were observed, as they have also been described in other AML cases with dmin.3, 6, 7 As these cytological features can also be observed at the diagnosis of promyelocytic leukaemia, the later entity was completely excluded after a negative polymerase chain reaction assay for the presence of promyelocytic leukaemia (PML)/retinoic acid receptor alpha (RARA) transcripts. Haematological cases with dmin are usually associated with a dismal prognosis. This could be explained in part by the notion that dmin are commonly found within complex karyotypes, although they have been reported as a sole cytogenetic abnormality as well.11 In addition, the presence of MYC amplifications in myeloid malignancies, as in our present cases, have been related with disease progression and resistance to chemotherapeutic drugs.12, 13 The biological mechanism behind the origin of dmin is not well understood. Despite that chromothripsis was initially proposed as a potential mechanism,14 in recent work analysing the architecture and expression pattern of amplicons involving chromosome 8q24 in AML, a step-wise evolution rather than a single-event origin, such as through chromothripsis, has been postulated. This notion was based in the observation that different MYC-dmin architectures can co-exist within the same leukaemic cell population, and also that dmin can evolve toward ring chromosomes.5 In conclusion, the presence of intracellular nuclear-like particles in blast cells from patients with MDS and AML should warn physicians of an adverse clinical outcome and prompt complementary genetic analysis. Finally, the co-existence of these specific morphological, cytogenetic and clinical features could point towards a singular clinicopathological entity, although larger series are needed to confirm this statement." @default.
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• W3040331102 date "2020-07-05" @default.
• W3040331102 modified "2023-09-28" @default.
• W3040331102 title "Micronuclei, dmin chromosomes and MYC amplifications as a singular presentation of myeloid malignancies" @default.
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• W3040331102 doi "https://doi.org/10.1111/bjh.16942" @default.
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