Gene expression and risk of leukemic transformation in myelodysplasia

Yusuke Shiozawa, Luca Malcovati, Anna Gallì, Andrea Pellagatti, Mohsen Karimi, Aiko Sato-Otsubo, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Kenichi Chiba, Hideki Makishima, Jacqueline Boultwood, Eva Hellström-Lindberg, Satoru Miyano, Mario Cazzola, Seishi Ogawa

Research output: Contribution to journalArticle

Abstract

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic disorders with a highly variable prognosis. To identify a gene expression–based classification of myelodysplasia with biological and clinical relevance, we performed a comprehensive transcriptomic analysis of myeloid neoplasms with dysplasia using transcriptome sequencing. Unsupervised clustering of gene expression data of bone marrow CD341 cells from 100 patients identified 2 subgroups. The first subtype was characterized by increased expression of genes related to erythroid/megakaryocytic (EMK) lineages, whereas the second subtype showed upregulation of genes related to immature progenitor (IMP) cells. Compared with the first so-called EMK subtype, the IMP subtype showed upregulation of many signaling pathways and downregulation of several pathways related to metabolism and DNA repair. The IMP subgroup was associated with a significantly shorter survival in both univariate (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.8-14; P 5 .002) and multivariate analysis (HR, 4.9; 95% CI, 1.3-19; P 5 .02). Leukemic transformation was limited to the IMP subgroup. The prognostic significance of our classification was validated in an independent cohort of 183 patients. We also constructed a model to predict the subgroups using gene expression profiles of unfractionated bone marrow mononuclear cells (BMMNCs). The model successfully predicted clinical outcomes in a test set of 114 patients with BMMNC samples. The addition of our classification to the clinical model improved prediction of patient outcomes. These results indicated biological and clinical relevance of our gene expression–based classification, which will improve risk prediction and treatment stratification of MDS.

Original languageEnglish
Pages (from-to)2642-2653
Number of pages12
JournalBlood
Volume130
Issue number24
DOIs
Publication statusPublished - Dec 14 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Shiozawa, Y., Malcovati, L., Gallì, A., Pellagatti, A., Karimi, M., Sato-Otsubo, A., Sato, Y., Suzuki, H., Yoshizato, T., Yoshida, K., Shiraishi, Y., Chiba, K., Makishima, H., Boultwood, J., Hellström-Lindberg, E., Miyano, S., Cazzola, M., & Ogawa, S. (2017). Gene expression and risk of leukemic transformation in myelodysplasia. Blood, 130(24), 2642-2653. https://doi.org/10.1182/blood-2017-05-783050