Chronic Eosinophilic Leukaemia Associated with JAK2 Exon 13 Insertion/Deletion Mutations.

Chronic eosinophilic leukaemia, not otherwise specified (CEL, NOS), is a diagnosis of exclusion made in cases in which there is clonal eosinophilia but an absence of genetic aberrations that define other disease subtypes. There is a need for further characterization of these cases in order to inform risk stratification and management. The importance of JAK2 mutations in myeloproliferative neoplasms (MPN) as a whole is well established, although their role specifically in eosinophilic disorders is less clear, with only a minority of cases demonstrating JAK2 abnormalities. Here, we report 2 cases with an exon 13 insertion-deletion (indel) mutation in JAK2: one with CEL-NOS and the second with an unspecified eosinophilic disorder. JAK2 indels were not detected in a screen of suspected MPN cases (n = 592) without eosinophilia that tested negative for common MPN driver mutations. Our findings thus provide further evidence for a specific association between this rare mutation and clonal eosinophilic disorders.

Acquired Bernard-Soulier syndrome and hypodysfibrinogenaemia because of multiple myeloma.

We describe a case of a patient with multiple myeloma with initial presentation simulating a bleeding disorder. Detailed coagulation work-up showed hypodysfibrinogenaemia along with a platelet function defect consistent with acquired Bernard-Soulier syndrome (BSS). Multiple plasma exchanges led to significant improvement in his bleeding symptoms. To the best of our knowledge, this is the first described case of simultaneous presentation of hypodysfibrinogenaemia and BSS secondary to multiple myeloma.

Androgen-regulation of the protein tyrosine phosphatase PTPRR activates ERK1/2 signalling in prostate cancer cells.

BACKGROUND: Androgens drive the onset and progression of prostate cancer (PCa) via androgen receptor (AR) signalling. The principal treatment for PCa is androgen deprivation therapy, although the majority of patients eventually develop a lethal castrate-resistant form of the disease, where despite low serum testosterone levels AR signalling persists. Advanced PCa often has hyper-activated RAS/ERK1/2 signalling thought to be due to loss of function of key negative regulators of the pathway, the details of which are not fully understood. METHODS: We recently carried out a genome-wide study and identified a subset of 226 novel androgen-regulated genes (PLOS ONE 6:e29088, 2011). In this study we have meta-analysed this dataset with genes and pathways frequently mutated in PCa to identify androgen-responsive regulators of the RAS/ERK1/2 pathway. RESULTS: We find the PTGER4 and TSPYL2 genes are up-regulated by androgen stimulation and the ADCY1, OPKR1, TRIB1, SPRY1 and PTPRR are down-regulated by androgens. Further characterisation of PTPRR protein in LNCaP cells revealed it is an early and direct target of the androgen receptor which negatively regulates the RAS/ERK1/2 pathway and reduces cell proliferation in response to androgens. CONCLUSION: Our data suggest that loss of PTPRR in clinical PCa is one factor that might contribute to activation of the RAS/ERK1/2 pathway.

A novel androgen-regulated isoform of the TSC2 tumour suppressor gene increases cell proliferation.

TSC2 (Tuberous sclerosis complex 2) is an important tumour suppressor gene, mutations within which are linked to the development of tuberous sclerosis and implicated in multiple tumour types. TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth. Here, we report the characterisation of a novel isoform of TSC2 which is under direct control of the ligand-activated androgen receptor. TSC2 isoform A (TSC2A) is derived from an internal androgen-regulated alternative promoter and encodes a 508-amino acid cytoplasmic protein corresponding to the C-terminal region of full-length TSC2, lacking the interaction domain for TSC1 and containing an incomplete interaction domain required for Rheb inactivation. Expression of TSC2A is induced in response to androgens and full-length TSC2 is co-ordinately down-regulated, indicating an androgen-driven switch in TSC2 protein isoforms. In contrast to the well-characterised suppressive effect on cell proliferation of full-length TSC2 protein, both LNCaP and HEK293 cells over-expressing TSC2 isoform A proliferate more rapidly (measured by MTT assays) and have increased levels of cells in S-phase (measured by both Edu staining and FACS analysis). Our work indicates, for the first time, a novel role for this well-known tumour suppressor gene, which encodes an activator of cell proliferation in response to androgen stimulation.