Expression studies in patients with Shwachman Diamond syndrome in relation to clonal chromosome anomalies in bone marrow

Shwachman-Diamond syndrome (SDS), autosomal recessive bone marrow failure condition, implies a high risk of developing myelodysplastic syndrome and acute myeloid leukaemia. Two clonal chromosome changes are frequent in the bone marrow (BM): an isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q). Both these clonal anomalies were shown to imply a positive prognostic role, due to the duplication of a mutation with milder effect, in the i(7)(q10), and to the loss of the EIF6 gene, in del(20)(q). Since 1999, we follow-up 97 Italian patients with SDS. We report the expression analysis of bone marrow (BM) cells of patients with SDS, in relation to the presence of clonal chromosome anomalies: del(20)(q) (five cases), i(7)(q10) (one case), other anomalies (two cases). The study was performed by microarray technique considering the whole transcriptome (WT), and three gene subsets, selected as relevant in BM functions. The results were compared with those of nine patients with SDS without clonal anomalies, and of nine healthy subjects. There is a significant difference between gene expression in BM of SDS patients and healthy subjects, both at level of WT and of the gene sets selected. The deletion del(20)(q), with the gene EIF6 consistently lost, even in patients with the smallest losses of material, changes the transcription pattern: a low proportion of abnormal cells lead to a pattern similar to SDS patients without acquired anomalies, whereas a high proportion yields to a pattern similar to healthy subjects. Hence, the benign prognostic value of the del(20)(q). The only case of i(7)(q10) showed a transcription pattern similar to healthy subjects, paralleling the positive prognostic role of this anomaly as well.