Clinicopathologic and molecular characterization of myeloid neoplasms harboring isochromosome 17(q10)
Authors: Valeria Visconte, Ali Tabarroki, Li Zhang, Edy Hasrouni, Chris Gerace, Robyn Frum, Jing Ai, Anjali S. Advani, Hien K. Duong, Matt Kalaycio, Yogen Saunthararajah, Mikkael A. Sekeres, Eric D. His, Shashirekha Shetty, Heesun J. Rogers, Ramon V. Tiu
Journal: American Journal of Hematology (2014)

Isochromosome 17(q10) [i(17)(q10)] is a product of the breakage or inappropriate division of the pericentromere leading to the duplication of the long arms and loss of the short arm of the chromosome 17. 1 In hematologic malignancies, it is detected mostly in the blast phase of chronic myeloid leukemia (CML), and less frequently in myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and acute myeloid leukemia (AML). Patients carrying i(17)(q10) usually have advanced stage of hematologic diseases, respond poorly to pharmacologic treatments, and have poor overall survival (OS). 2 The underlying mechanism leading to these poor outcomes is not known. The identification of specific molecular mutations in distinct disease subtypes has advanced our understanding of disease pathogenesis. For example, SF3B1 mutations in the case of ring sideroblasts in refractory anemia with ring sideroblasts and SRSF2 mutations in the monocytic phenotype of chronic myelomonocytic leukemia. To date, the molecular defects present in patients with myeloid neoplasms carrying i(17)(q10) have not been described. Here, we first described the clinicopathologic characteristics and outcomes of 21 patients with myeloid neoplasms who harbored i(17)(q10) including AML, MDS, and/or MPN (Table 1). All BCR/ABL1 positive CML patients were excluded in this study. We then characterized the molecular defects of 15 patients who had available DNA samples. The mutational status of 12/15 (80%) patients was evaluated for 21 relevant genes in the pathogenesis of myeloid neoplasms. 3, 4 For the remaining three patients, limited DNA quality restricted the mutational analysis to only a few genes (SETBP1, NRAS, SF3B1). Patients in our cohort commonly had leukocytosis (57%), absolute monocytosis (43%), anemia (95%), and thrombocytopenia (86%). The bone marrow pathology review showed characteristic dysgranulopoiesis (100%) with nonsegmented round nuclei, ring form or pseudo-Pelger–Huet anomaly, dysmegakaryopoiesis (89%) with micromegakaryocytes, and dyserythropoiesis (35%) (Fig. 1a–c). Sanger sequencing showed that 9/15 (60%) of patients carry at least one mutation in one gene. Supporting Information Table 1 shows that the most commonly mutated genes are important in granulopoiesis and leukemogenesis. Indeed, SETBP1 and SRSF2 mutations were found in 6/15 (40%) and 5/12 (41.7%), respectively. TP53 mutations were found in 2/12 patients (16.7%). Similarly CSF3R, a gene mutated primarily in chronic neutrophilic leukemia, was found in 2/12 patients (16.7%). Patients with i(17)(q10) [(four isolated and two nonisolated i(17)(q10)] carrying SETBP1 mutations also carried concurrent SRSF2 (5/6; 83%), CSF3R (2/6; 33%), or TP53 (1/6; 17%) mutations. Twelve out of 15 patients were also completely genotyped for U2AF1, ASXL1, DNMT3A, IDH1/2, KRAS, EZH2, and CBL and were wild type (WT). In our cohort, patients with myeloid neoplasms and i(17)(q10) shared MDS/MPN features and a poor prognosis (median OS of 4 months with 90% of patients expired with a median follow-up of 4 months). No differences in OS were found between patients carrying i(17)(q10) as a sole abnormality or nonisolated i(17)(q10) (4.5 vs. 4.0 months; P = 0.164). We also observed a higher percentage (58.8%; 10/17) of leukemic transformation in MDS and/or MPN patients with i(17)(q10). In addition, patients carrying SETBP1 and/ or additional mutations in SRSF2, CSF3R, or TP53 tended to be older (median 75 vs. 67 years; P = 0.2) and had monocytosis (10.5 vs. 0.1 × 103/µl; P = 0.04) compared to WT patients. We also noted that the outcome of the patients with or without mutations remain poor with a trend toward worse OS in those with mutations (data not shown) Morphologically, all patients in our cohort showed dysgranulopoiesis more commonly as nonsegmented round nuclei or ring form similar to what was described by McClure et al. 5 which is different from the typically described pseudo-Pelger-Huet anomaly reported in other studies. 2, 6 However, these changes were not associated with any specific molecular profile. This may suggest that there are different morphological and possibly pathogenic subtypes of patients harboring i(17)(q10). In summary, SETBP1 and SRSF2 are the most common somatic genetic abnormalities in patients with myeloid neoplasms carrying i(17)(q10) and may be important drivers of disease pathogenesis. The assessment of the clinical impact of these mutations in this uncommon cytogenetic subtype is limited by the heterogeneity of the disease types. However, despite these limitations, the results of this study may provide important preliminary insights into the molecular pathogenesis of the disease. Further confirmation in a larger cohort of patients will help strengthen the molecular findings of this study. VV designed the study, carried out the experiments, analyzed and interpreted the data, and wrote the manuscript; AT collected the data, performed experiments; LZ performed bioinformatics analysis; EH, CG, RF, and JA performed experiments; ASA, HKD, MK, YS provided patient samples; MAS contributed to patients' samples and edited the manuscript; EDH provided patient samples and edited the manuscript; SS analyzed the data and edited the manuscript; HJR and RVT equally designed the study, analyzed and interpreted the data, and wrote the manuscript. All authors approved the submission of the manuscript. This study was a collaborative work of members of the Cleveland Clinic Cancer Cytogenomics Collaborative Research Working Group (CCCRWG). Valeria Visconte,1 Ali Tabarroki,1 Li Zhang,2 Edy Hasrouni,1 Chris Gerace,1 Robyn Frum,1 Jing Ai,1,3 Anjali S. Advani,1,3 Hien K. Duong,3 Matt Kalaycio,3 Yogen Saunthararajah,1,3 Mikkael A. Sekeres,1,3 Eric D. Hsi,4 Shashirekha Shetty,4 Heesun J. Rogers,4*† Ramon V. Tiu1,3*† 1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; 2University of California, San Francisco, School of Medicine, Department of Medicine, San Francisco, California; 3Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; 4Department of Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.