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 language | English (US) |
|---|---|
| Pages (from-to) | 3327-3335 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 123 |
| Issue number | 21 |
| DOIs | |
| State | Published - May 22 2014 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling
AU - Taskesen, Erdogan
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
PY - 2014/5/22
Y1 - 2014/5/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84901465471&partnerID=8YFLogxK
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U2 - 10.1182/blood-2013-07-512855
DO - 10.1182/blood-2013-07-512855
M3 - Article
C2 - 24668493
AN - SCOPUS:84901465471
VL - 123
SP - 3327
EP - 3335
JO - Blood
JF - Blood
SN - 0006-4971
IS - 21
ER -