Abstract

X-linked neutropenia (XLN, OMIM #300299)) was first described in 2001 in a three-generation Belgian family with five affected members and with a L270P gain-of-function mutation in the GTPase binding domain (GBD) of the Wiskott-Aldrich-syndrome protein (WASP) (

Nat Genet
2001
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27
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313
). Although all five L270P cases originally presented with neutropenia, two of them eventually developed a myeloid malignancy while under G-CSF, with monosomy 7 in the malignant cells. One male (II.3) developed a myelodysplastic syndrome (MDS-RAEB) at age 65, achieved stable remission after three courses of decitabine, but died three years later due to an unrelated cause. A second patient (III.6) succumbed to refractory MDS RAEB, rapidly evolving to MDS-RAEBt at age 38. Since our original report, two more cases with XLN have been reported, one with a I294T and one with a S272P WASP mutation. (Ancliff et al. Blood online 2006). The I294T case, 4 years old, had myelodysplastic features at presentation. These observations have prompted us to investigate whether inherited gain-of-function WASP mutations are associated with paediatric MDS or AML. In addition we have explored whether acquired WASP mutations occur in adult myeloid malignancies. 207 cases were examined. Male/female ratio was 1.35. 34 cases were between 2 months and 20 years old and 173 cases were between 21 and 89 years old. There were 48 cases with myelodysplasia, 157 had acute myeloid leukaemia and 2 had myelofibrosis. 29% had monosomy 7. There were two brothers with monosomy 7, one with AML M5 and the other with secondary ALL after MDS. Exons 7-10, encoding the GTPase Binding Domain (residues 230-381), were amplified and screened for mutations using dHPLC. In these 207 samples from patients with MDS or AML, no mutations were found in the exons 7-9 of the WAS gene. One mutation was found in intron 6 in a male patient with AML and monosomy 7. The mutation did not influence splicing of the exon and was thus considered irrelevant. Four patients had a known T1029C (V332A) single nucleotide polymorphism in exon 10. One patient with AML (age 50y) had a C975T (P314S) mutation in exon 10, which has not been reported previously. Since this mutation occurs in less than 1%, it does not qualify as a polymorphism. If relevant for the pathogenesis of AML, the mutation is very rare whatsoever. Although the eventual risk of malignant myeloid transformation appears to be increased in L270P XLN, we could not, with one exception, identify mutations in exons 7-10 of the WAS gene in this series of paediatric and adult MDS/AML. Therefore, inherited or acquired WAS mutations do not seem to be commonly associated with pediatric or adult MDS or AML. Our data therefore do not support screening for exon 7-10 mutations of WAS in the context of paediatric or adult MDS and AML.

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