Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

H. Dolatshad, A. Pellagatti, M. Fernandez-Mercado, B. H. Yip, L. Malcovati, M. Attwood, B. Przychodzen, N. Sahgal, A. A. Kanapin, H. Lockstone, L. Scifo, P. Vandenberghe, E. Papaemmanuil, C. W J Smith, P. J. Campbell, S. Ogawa, J. P. Maciejewski, M. Cazzola, K. I. Savage, J. Boultwood

Research output: Contribution to journalArticle

Abstract

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34 + cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript andor exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicingprocessing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expressionsplicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34 + cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processespathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

Original languageEnglish
Pages (from-to)1092-1103
Number of pages12
JournalLeukemia
Volume29
Issue number5
DOIs
Publication statusPublished - May 11 2015

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Myelodysplastic Syndromes
Hematopoietic Stem Cells
Refractory Anemia
Genes
RNA
RNA Sequence Analysis
Mutation
Myeloid Cells
Cell Cycle Checkpoints
Transcriptome
DNA Damage
Exons
Cell Cycle
Homeostasis
Iron
Gene Expression
Cell Line
Growth
Proteins

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. / Dolatshad, H.; Pellagatti, A.; Fernandez-Mercado, M.; Yip, B. H.; Malcovati, L.; Attwood, M.; Przychodzen, B.; Sahgal, N.; Kanapin, A. A.; Lockstone, H.; Scifo, L.; Vandenberghe, P.; Papaemmanuil, E.; Smith, C. W J; Campbell, P. J.; Ogawa, S.; Maciejewski, J. P.; Cazzola, M.; Savage, K. I.; Boultwood, J.

In: Leukemia, Vol. 29, No. 5, 11.05.2015, p. 1092-1103.

Research output: Contribution to journalArticle

Dolatshad, H, Pellagatti, A, Fernandez-Mercado, M, Yip, BH, Malcovati, L, Attwood, M, Przychodzen, B, Sahgal, N, Kanapin, AA, Lockstone, H, Scifo, L, Vandenberghe, P, Papaemmanuil, E, Smith, CWJ, Campbell, PJ, Ogawa, S, Maciejewski, JP, Cazzola, M, Savage, KI & Boultwood, J 2015, 'Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells', Leukemia, vol. 29, no. 5, pp. 1092-1103. https://doi.org/10.1038/leu.2014.331
Dolatshad, H. ; Pellagatti, A. ; Fernandez-Mercado, M. ; Yip, B. H. ; Malcovati, L. ; Attwood, M. ; Przychodzen, B. ; Sahgal, N. ; Kanapin, A. A. ; Lockstone, H. ; Scifo, L. ; Vandenberghe, P. ; Papaemmanuil, E. ; Smith, C. W J ; Campbell, P. J. ; Ogawa, S. ; Maciejewski, J. P. ; Cazzola, M. ; Savage, K. I. ; Boultwood, J. / Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. In: Leukemia. 2015 ; Vol. 29, No. 5. pp. 1092-1103.
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AU - Fernandez-Mercado, M.

AU - Yip, B. H.

AU - Malcovati, L.

AU - Attwood, M.

AU - Przychodzen, B.

AU - Sahgal, N.

AU - Kanapin, A. A.

AU - Lockstone, H.

AU - Scifo, L.

AU - Vandenberghe, P.

AU - Papaemmanuil, E.

AU - Smith, C. W J

AU - Campbell, P. J.

AU - Ogawa, S.

AU - Maciejewski, J. P.

AU - Cazzola, M.

AU - Savage, K. I.

AU - Boultwood, J.

PY - 2015/5/11

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