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The landscape of myeloid neoplasms with isochromosome 17q discloses a specific mutation profile and is characterized by an accumulation of prognostically adverse molecular markers

Subjects

Isochromosome 17 (i(17)(q10)) is a rare cytogenetic abnormality resulting in the loss of the short arm and duplication of the long arm of chromosome 17.1 I(17)(q10) has been reported in different myeloid neoplasms, like acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap, as well as in Hodgkin lymphoma and other lymphomas.2 I(17)(q10) has been described both as primary and as secondary chromosomal aberration. The overall frequency is low with 1–2% in entities other than CML.3 However, in accelerated phase or blast crises of CML i(17)(q10) has been identified as frequently occurring secondary aberration, indicating a poor prognosis. Usually i(17)(q10) occurs in a complex karyotype, but is also found as sole abnormality as well as with one additional aberration. It is believed that i(17)(q10) as a sole abnormality in myeloid neoplasms defines a distinctive clinicopathological entity with high risk of leukemic progression and poor prognosis,4, 5 although it is specifically mentioned only briefly in the WHO classification.6 The description of myeloid neoplasms that carry a i(17)(q10) and have <20% blasts remains difficult. Patients show mixed features of myeloproliferation and dysplasia, associated with pseudo-Pelger-Huet anomaly of the neutrophils.2, 4 Most cases show a prominent monocytic component and therefore might meet criteria for chronic myelomonocytic leukemia (CMML). However, often the designation to MDS/MPN, unclassifiable with isolated i(17)(q10) is most appropriate.6 Therefore, we aimed at comprehensively characterizing the molecular features of patients with myeloid neoplasms and i(17)(q10).

To address this issue we selected patients by the presence of i(17)(q10) and diagnosis of a myeloid neoplasm (n=62), but excluded patients with BCR-ABL1/Philadelphia positive CML. The selected cohort comprised of 47 males and 15 females with a median age of 69 years (range: 30–87 years). Classification of all cases was performed by cytomorphology on peripheral blood and/or bone marrow smears according to the WHO classification.6 All samples were analyzed by next generation sequencing using a 29-gene panel targeting ASXL1, BCOR, BRAF, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1. Variants of unknown significance were excluded from statistical analyses (n=14). Chromosome banding and fluorescence in situ hybridization analysis were performed in all cases, a subset of cases with sole i(17)(q10) were additionally analyzed by array CGH (19/27). For further patient characteristics as well as methodical details see Supplementary Information.

Following the WHO classification, four patients were diagnosed as MPN, 13 as MDS/MPN overlap, 24 as MDS and 21 as AML. Cytogenetic analyses revealed 27 cases with i(17)(q10) as sole abnormality, while 23 cases showed additional chromosome aberrations and eight even a complex karyotype (>3 aberrations). Further four cases had two independent cell clones, with one harboring the sole i(17)(q10) abnormality. To address the question, if patients with i(17)(q10) as sole abnormality harbor small additional lesions, we analyzed 19/27 such cases by array CGH, which revealed 15/19 cases with i(17)(q10) only. Four patients showed additional submicroscopic aberrations (1–3 per patient): loss of 7q22.1, loss of 12p13.31p12.3, loss of 17q11.2q12, CN-LOH 19p13.3p11, CN-LOH 22q12.3q13.33 and 22q11.22q13.33 (Supplementary Figure S1). One of these patients showed additionally a monosomy 7 and trisomy 13, not detectable by chromosome banding potentially due to no proliferation of the respective cells.

The comprehensive mutational analyses resulted in 59/62 patients (95%) carrying at least one mutation, while a median of three mutations per patient was observed (range 0–6). The three most frequently mutated genes were ASXL1 (66%, 41/62), SRSF2 (65%, 40/62) and SETBP1 (48%, 30/62) (Figure 1). These mutations are not specific for cases with i(17)(q10) as they have been identified across the spectrum of myeloid neoplasms, including MDS, MPN or MDS/MPN overlap syndromes irrespective of cytogenetic background. ASXL1 is a chromatin modifier belonging to the group of epigenetic regulation and is known to be frequently mutated in MDS patients.7 SRSF2 is a component of the splicing machinery and mutations therein were frequently found in CMML patients.8, 9 SRSF2 is located on chromosome 17q25.1, resulting in three copies in patients with i(17)(q10) abnormality. Therefore, it is an interesting candidate gene for causing clinicopathologic features by a mechanism inverse to the one known for TP53 – located on chromosome 17p13.1 – that is only present with one copy in patients with i(17)(q10). The identification of mutations in SETBP1 recently presented a molecular marker in atypical chronic myeloid leukemia, although the function of SETBP1 protein is not fully understood.10 SETBP1 mutations have also been identified in different myeloid malignancies, showing association with mutations in ASXL1 and CBL, as well as the cytogenetic abnormality monosomy 7 and as further investigated here with i(17)(q10).11 The results of the present study are in line with these recent findings, although mutations in ASXL1, SRSF2 and SETBP1 showed no association to any WHO entity. All three genes have been shown to adversely influence prognosis.9, 10, 12, 13 Further, the following genes were mutated at frequencies 10%: TET2 (24%), ETV6 (16%), CBL (13%), TP53 (15%), RUNX1 (11%) and NRAS (10%). Most of these genes are known for adverse prognostic impact in MDS and MDS/MPN overlap.12, 14 The high incidence of SRSF2, SETBP1 and TP53 mutations go in line with previously described findings of mutations in these genes in cases with i(17)(q10), while other frequencies slightly differ, maybe due to relatively small case numbers in other studies.15 Reviewing the bone marrow morphology showed the characteristic pseudo-Pelger-Huet anomaly in 61% (36/59), micromegakaryocytes in 42% (26/62) and dyserythopoiesis in 19% (12/62) of cases, going in line with reported morphological findings.2, 4, 15 Although these changes were not associated with the cytogenetic profile, that is, sole i(17)(q10) or with additional cytogenetic aberrations, respectively, pseudo-Pelger-Huet anomaly showed a trend towards co-occurrence with ASXL1 mutations (27/39 in ASXL1 mut vs 9/20 ASXL1 wild type (wt) P=0.094).

Figure 1
figure1

Molecular, cytogenetic and morphological characterization of patients with i(17)(q10). Illustration of all 62 samples, each column represents one patient. All 29 analyzed genes as well as occurrence of i(17)(q10) as sole aberration or with additional cytogenetic aberrations, as well as the presence of pseudo-Pelger-Huet anomaly are given for each patient. Light gray: not mutated, red: mutated, orange: variant, black: i(17)(q10) sole, purple: pseudo-Pelger-Huet present. The different entities are colored as follows: light gray: MPN, dark gray: AML, green: MDS/MPN overlap and blue: MDS. White: no data available.

Interestingly, addressing the concomitant occurrence of gene mutations showed that mutations in the three most frequently mutated genes ASXL1, SRSF2 and SETBP1 often co-occurred (n=21/62; 34%). A total of 52/62 (84%) patients showed at least one mutation in one of these three genes. In more detail, ASXL1 and SRSF2 were rarely mutated alone (9/41; 5/40), while SETBP1 was even never mutated solely (0/30), indicating acquirement of SETBP1 mutations during disease course in patients with i(17)(q10). Consequently, SETBP1 mutations associated significantly with mutations in ASXL1 as well as SRSF2 (24/41 vs 6/21 in ASXL1 wt, P=0.033; 27/40 vs 3/22 in SRSF2 wt, P<0.001) (Figure 2a). Furthermore, cases harboring mutations in all three genes ASXL1, SRSF2 and SETBP1 associated with isolated i(17)(q10) (13/27 vs 8/35, P=0.058), most prominent in MDS cases (6/10 vs 2/12, P=0.032). This indicates that these three mutations might be drivers of disease pathogenesis in this cytogenetic background. Analyzing the occurrence of cases with all three genes mutated within the different myeloid entities in our cohort, showed that this genetic phenotype is present in MPN (n=1/21), MDS/MPN overlap (n=6/21), MDS (n=8/21), as well as AML (n=6/21). The morphological diversity of cases with i(17)(q10) is therefore likely to be the result of distinct mutational patterns, for which the number and order of mutations may play a pivotal role.

Figure 2
figure2

Comparison of mutation distribution and prognostic impact in cases with and without i(17)(q10). Venn diagrams illustrating the distribution of concomitant mutations in ASXL1, SRSF2 and SETBP1 in the i(17)(q10) cohort (a) and the matched control cohort (b). Case numbers are given for all combinations. For comparison case numbers are also given relative to the cohort (%), that shows at least one mutation in either ASXL1, SRSF2 or SETBP1 (n=52 (a) and n=278 (b), respectively). (c) Kaplan–Meier plots illustrating the negative impact of i(17)(q10) in the total cohort (left graph), within SRSF2 mutated cases (middle graph), and SETBP1 mutated cases (right graph). Case numbers and P-values are indicated, OS is given in months.

To evaluate if this genetic profile is specific for cases with i(17)(q10) aberration, we assembled a matched control cohort comprising of 278 patients with different myeloid malignancies and at least one mutation in either ASXL1, SRSF2 or SETBP1, but no i(17)(q10) cytogenetic aberration. We compared this cohort with cases of the i(17)(q10) cohort, showing at least one mutation in ASXL1, SRSF2 or SETBP1 (n=52). For further patient characteristics see Supplementary Information.

In the total control cohort ASXL1 was mutated in 199/278 (72%), SRSF2 in 156/278 (56%) and SETBP1 in only 53/278 (19%) cases (Figure 2b). Therefore, SRSF2 is slightly less and SETBP1 is less frequently mutated in myeloid cases without i(17)(q10), while ASXL1 is often mutated in both addressed cohorts. A total of 170/278 (61%) patients carried one mutation within these three investigated genes, while 86/278 (31%) cases showed two, and in only 22/278 (8%) all three analyzed genes were mutated. This demonstrates that this genetic phenotype with all three genes being mutated occurs significantly more often in cases with i(17)(q10) aberration (40% (21/52) vs 8% (22/287), P<0.001). In comparison, SETBP1 as a single mutation was found in the control cohort but never alone in the i(17)(q10) cohort. Even more in the latter cohort, it was only found to be mutated in the coincidence with ASXL1 and/or SRSF2. Addressing the prognostic impact revealed that i(17)(q10) has the strongest negative influence on overall survival (OS) (P=0.025). This is still true in subcohorts with SRSF2 or SETBP1 mutations (P=0.005 and P=0.022, respectively, Figure 2c). However, SETBP1 mutated cases without i(17)(q10) also demonstrated an inferior OS, what was not observed for SRSF2 mutations without i(17)(q10) (Supplementary Figure S2).

The presented data supports the hypothesis that myeloid neoplasms with i(17)(q10) and mutations in ASXL1, SRSF2 and SETBP1 represent a unique genetically defined subtype with adverse prognosis, characterized by the accumulation of molecular events. In addition, these cases harbor mutations, known from other myeloid neoplasms, possibly defining the entity.

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Acknowledgements

We thank all clinicians for sending samples to our laboratory for diagnostic purposes and for providing clinical information and follow-up data. In addition, we would like to thank all the co-workers at the MLL Munich Leukemia Laboratory for approaching together many aspects in the field of leukemia diagnostics and research.

Author contributions

MM investigated molecular mutations, analyzed the data and wrote the manuscript; CH was responsible for cytogenetics; WK was involved in statistical analyses; MZ performed array CGH; KM characterized morphological findings; TH was responsible for cytomorphologic analysis and was involved in the collection of clinical data as well as manuscript preparation. All authors read and contributed to the final version of the manuscript.

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Correspondence to M Meggendorfer.

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CH, WK and TH declare equity ownership of MLL Munich Leukemia Laboratory. MM, MZ and KM are employed by MLL Munich Leukemia Laboratory.

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Supplementary Information accompanies this paper on the Leukemia website

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Meggendorfer, M., Haferlach, C., Zenger, M. et al. The landscape of myeloid neoplasms with isochromosome 17q discloses a specific mutation profile and is characterized by an accumulation of prognostically adverse molecular markers. Leukemia 30, 1624–1627 (2016). https://doi.org/10.1038/leu.2016.21

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