Genome-wide DNA profiling identifies a stable profile although with aberrations targeting the fibroblast growth factor pathway in hairy cell leukemia

Hairy cell leukemia (HCL) is a rare B-cell neoplasm with largely unravelled features of lymphomagenesis. Molecular mechanisms of disease are largely unknown and genomic aberrations have infrequently been investigated in HCL. In order to elucidate the genetic mechanisms of HCL pathogenesis, we analyzed copy number changes and loss of heterozigosity (LOH) by genome wide DNA profiling with the Affymetrix Human Mapping 250k Nsp arrays in 16 HCL. All investigated cases expressed multiple pre- (IgM+/−D) and post-switch (IgG+/−A) isotypes. Tumor IGHV gene transcript homology to germline ranged from 88.4 to 98.6%, with 4/16 HCL having >98% homology. Four of 16 patients were refractory or had progressive disease after first line purine-analogue-based treatments. CD103+ve hairy cells were >60% in all test samples. Genome wide DNA profiling demonstrated gross non recurrent copy number deletions in only 4/16 cases (25%), affecting 14q24-q32, 3q23, 3q27.3-q29, 8p12-pter 10q21-q23, 10q25-q26, 17p11-pter, 17q11-q21, 17q22–23, Xp21.2-p22.11, Xq13.3, Xq21.1-q21.33, Xq22.2–q28, the whole chromosomes 21 and X. Five of 16 patients (31%) presented LOH. Most interestingly, the 5 patients showed LOH regions, with a region of overlap in two patients at 6q25.1, without any copy number changes, indicative of uniparental disomy. Genes involved in bone marrow fibrosis, multiple isotype expression and response to treatment were specifically investigated. Interestingly, among genes critical for fibrosis, FGF12, a member of the fibroblast growth factors family, was specifically targeted by a complex chromosomal rearrangement at 3q27.3-q29, and reverse transcript-polymerase chain reaction confirmed FGF12 transcript expression. Among genes associated with poor response, p53 deletion was documented in a non-responder HCL. Conversely, no abnormalities at 14q32 locus (duplications or gains) were observed at IgH 14q32 region in these multiple IgH isotype expressing HCL. Overall, our analysis showed a highly stable genome with lack of gross recurrent abnormalities, which is an additional unique feature of HCL among B-cell neoplasms. However, our genomic analyses were able to identify specific chromosomal rearrangements targeting genes involved in fibrosis. Lack of gains of 14q32 locus was consistent with our hypothesis that multiple IgH isotypes are generated at RNA level in multiple IgH expressing HCL. The present analysis provides the basis for further molecular and epigenetic investigations.