Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling

Erdogan Taskesen, Marije Havermans, Kirsten Van Lom, Mathijs A. Sanders, Yvette Van Norden, Eric Bindels, Remco Hoogenboezem, Marcel J T Reinders, Maria Figueroa, Peter J M Valk, Bob Löwenberg, Ari Melnick, Ruud Delwel

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Mutations in splice factor (SF) genes occurmore frequently inmyelodysplastic syndromes (MDS) than in acute myeloid leukemias (AML). We sequenced complementary DNA from bonemarrowof 47 refractory anemiawithexcess blasts (RAEB) patients, 29AML cases with low marrow blast cell count, and 325 other AML patients and determined the presence of SFhotspot mutations in SF3B1, U2AF35, and SRSF2. SFmutations were found in 10 RAEB, 12 AML cases with low marrow blast cell count, and 25 other AML cases. Our study provides evidence that SF-mutant RAEB and SF-mutant AML are clinically, cytologically, and molecularly highly similar. An integrated analysis of genomewidemessenger RNA (mRNA) expression profiling and DNA-methylation profiling data revealed 2 unique patient clusters highly enriched for SF-mutant RAEB/AML. The combined genomewide mRNA expression profiling/DNA-methylation profiling signatures revealed 1 SF-mutant patient clusterwith an erythroid signature. The other SF-mutant patient cluster was enriched for NRAS/KRAS mutations and showed an inferior survival.We conclude that SF-mutant RAEB/AML constitutes a related disorder overriding the artificial separation between AML and MDS, and that SF-mutant RAEB/AML is composed of 2 molecularly and clinically distinct subgroups.We conclude that SF-mutant disorders should be considered as myeloid malignancies that transcend the boundaries of AML and MDS.

Original languageEnglish (US)
Pages (from-to)3327-3335
Number of pages9
JournalBlood
Volume123
Issue number21
DOIs
StatePublished - May 22 2014
Externally publishedYes

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DNA Fingerprinting
DNA Methylation
Acute Myeloid Leukemia
Gene expression
Refractory materials
Leukemia
Gene Expression
Messenger RNA
Mutation
Cell Count
Bone Marrow
Complementary DNA
Genes
RNA
Survival

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Taskesen, E., Havermans, M., Van Lom, K., Sanders, M. A., Van Norden, Y., Bindels, E., ... Delwel, R. (2014). Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling. Blood, 123(21), 3327-3335. https://doi.org/10.1182/blood-2013-07-512855

Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling. / Taskesen, Erdogan; Havermans, Marije; Van Lom, Kirsten; Sanders, Mathijs A.; Van Norden, Yvette; Bindels, Eric; Hoogenboezem, Remco; Reinders, Marcel J T; Figueroa, Maria; Valk, Peter J M; Löwenberg, Bob; Melnick, Ari; Delwel, Ruud.

In: Blood, Vol. 123, No. 21, 22.05.2014, p. 3327-3335.

Research output: Contribution to journalArticle

Taskesen, E, Havermans, M, Van Lom, K, Sanders, MA, Van Norden, Y, Bindels, E, Hoogenboezem, R, Reinders, MJT, Figueroa, M, Valk, PJM, Löwenberg, B, Melnick, A & Delwel, R 2014, 'Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling', Blood, vol. 123, no. 21, pp. 3327-3335. https://doi.org/10.1182/blood-2013-07-512855
Taskesen, Erdogan ; Havermans, Marije ; Van Lom, Kirsten ; Sanders, Mathijs A. ; Van Norden, Yvette ; Bindels, Eric ; Hoogenboezem, Remco ; Reinders, Marcel J T ; Figueroa, Maria ; Valk, Peter J M ; Löwenberg, Bob ; Melnick, Ari ; Delwel, Ruud. / Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling. In: Blood. 2014 ; Vol. 123, No. 21. pp. 3327-3335.
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AU - Havermans, Marije

AU - Van Lom, Kirsten

AU - Sanders, Mathijs A.

AU - Van Norden, Yvette

AU - Bindels, Eric

AU - Hoogenboezem, Remco

AU - Reinders, Marcel J T

AU - Figueroa, Maria

AU - Valk, Peter J M

AU - Löwenberg, Bob

AU - Melnick, Ari

AU - Delwel, Ruud

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