Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110–FGFR1 fusion: Report of a new case and review of the literature

International audienceThe 8p12 myeloproliferative syndrome is a rare, generally aggressive chronic myeloproliferative disorder (MPD). The hallmark of this MPD is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. In MPD cells FGFR1 is fused to several partners. The most frequent partner genes are BCR, CEP110, FOP, and ZNF198, localized on 22q11, 9q33, 6q27, and 13q12, respectively. We report here the tenth case of translocation (8;9)(p12;q33) in an acute myelomonocytic leukemia and provide a review of the literature that points to common syndrome features: the t(8;9)(p11;q33) MPD transforms rapidly, and always in myelomonocytic leukemia, with a possible B- or T-lymphoid involvement, which may include tonsil invasion. The FGFR1-MPD seems refractory to current chemotherapies and is not sensitive to imatinib. Currently, only the patients with bone marrow transplantation stand a chance of survival

Variant MYST4-CBP gene fusion in a t(10;16) acute myeloid leukaemia

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γ-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line

International audiencegamma-heregulin is a recently described novel isoform of the heregulin/neuregulin class of EGF-like ligands that bind to and activate receptors of the ErbB family. Deregulated signaling through the heregulin-ErbB pathway is thought to be implicated in the development of a subset of human breast cancers. gamma-heregulin has been found to be expressed in the culture supernatant of MDA-MB-175, a breast carcinoma cell line. gamma-heregulin is characterized by the presence of a large N-terminal peptide extension that is not found in other heregulin isoforms. Here we report that this unique N-terminal extension of gamma-heregulin is identical to the N-terminus of DOC4, a product of a recently identified CHOP-dependent stress-induced gene. Human DOC4 and the heregulin-encoding genes map to different chromosomes and the MDA-MB-175 cell line contains a chromosomal translocation that leads to the fusion of DOC4 and HGL, on chromosomes 11 and 8, respectively. Thus, gamma-heregulin is a product of a mutant fusion gene and not a bona fide normal isoform. We speculate that the mutation may be selected for by virtue of its ability to activate ErbB signaling through the production of an autocrine ligand

A gene expression signature of primary resistance to imatinib in chronic myeloid leukemia

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Comparative multi-methodological measurement of ERBB2 status in breast cancer

International audienceThe ERBB2 transmembrane tyrosine kinase receptor is both a prognostic marker and a therapeutic target in breast cancer. Accurate determination of ERBB2 status is a prerequisite for the establishment of prognostic significance and for the selection of ERBB2-overexpressing breast tumours for specific treatment. Unfortunately, there is no complete agreement on how this determination should be performed. This study has compared four methods of assessment of ERBB2 status. Two global, extraction-based methods using real-time quantitative PCR on DNA (Q-PCR) or RNA (RQ-PCR) and two non-global, tissue-based methods, ie fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), were used. The 94 breast cancers tested were enriched in cases scoring 2+ using the IHC scoring system currently in use and for which the actual ERBB2 status remains ill defined. To determine the best parameters and reagents for assessment, two protocols for FISH and five anti-ERBB2 antibodies were used, and both FISH and IHC were carried out on the same tissue microarrays (TMAs). It is shown that the combination of the two tissue-based methods gives the best results. The use of either PCR-based method did not improve the results significantly. A new combined IHC score based on the association of two selected anti-ERBB2 antibodies (HercepTest trade mark and TAB250) and a dual scale for improved assessment of ERBB2 protein expression, particularly in 2+ cases, are proposed

Rearrangements involving 12q in myeloproliferative disorders: possible role of HMGA2 and SOCS2 genes

International audienceWe report two cases of translocation associated with deletion on derivative chromosomes in atypical myeloproliferative disorder (MPD). In a MPD with t(3;12)(q29;q14), the rearrangement targeted the HMGA2 locus at 12q14 and deleted a region of about 1.5 megabases (Mb) at 3q29. In an MPD with t(9;12)(q13 approximately q21;q22) and JAK2 V617F mutation, array comparative genomic hybridization delineated a deletion of about 3 Mb at 9q13 approximately q21 and a deletion of about 2 Mb at 12q22 containing SOCS2. These results show that close examination of translocations in hematopoietic diseases may reveal associated microdeletions. The role of these deletions is discussed

Combined translocation with ZNF198-FGFR1 gene fusion and deletion of potential tumor suppressors in a myeloproliferative disorder

International audienceTyrosine kinases activated by mutation or translocation are involved in the chronic phase of myeloproliferative disorders. Complementary or alternative events are not so well characterized. We report here a case of t(8;13) generating a ZNF198-FGFR1 fusion kinase gene on the derivative chromosome 13. ZNF198-FGFR1 mRNA, but not FGFR1-ZNF198, was detected by polymerase chain reaction amplification. By using fluorescence in situ hybridization with BAC clones, we mapped a deletion of about 2 megabases on the derivative chromosome 8, including the reciprocal FGFR1-ZNF198 fusion gene and the surrounding genes from 8p11 and 13q12. Potential tumor suppressor genes affected by the deletion by loss (IFT88, CRYL1, TACC1) or break (LATS2) may participate in the malignant process

Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia

International audienceThe myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal haematological diseases characterized by ineffective haematopoiesis and predisposition to acute myeloid leukaemia (AML). The pathophysiology of MDSs remains unclear. A definition of the molecular biology of MDSs may lead to a better classification, new prognosis indicators and new treatments. We studied a series of 40 MDS/AML samples by high-density array-comparative genome hybridization (aCGH). The genome of MDSs displayed a few alterations that can point to candidate genes, which potentially regulate histone modifications and WNT pathways (e.g. ASXL1, ASXL2, UTX, CXXC4, CXXC5, TET2, TET3). To validate some of these candidates we studied the sequence of ASXL1. We found mutations in the ASXL1 gene in four out of 35 MDS patients (11%). To extend these results we searched for mutations of ASXL1 in a series of chronic myelomonocytic leukaemias, a disease classified as MDS/Myeloproliferative disorder, and found mutations in 17 out of 39 patients (43%). These results show that ASXL1 might play the role of a tumour suppressor in myeloid malignancies

A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/ NRG1 gene

International audienceThe 8p11-21 region is a frequent target of alterations in breast cancer and other carcinomas. We surveyed 34 breast tumor cell lines and 9 pancreatic cancer cell lines for alterations of this region by use of multicolor fluorescence in situ hybridization (M-FISH) and BAC-specific FISH. We describe a recurrent chromosome translocation breakpoint that targets the NRG1 gene on 8p12. NRG1 encodes growth factors of the neuregulin/heregulin-1 family that are ligands for tyrosine kinase receptors of the ERBB family. Breakpoints within the NRG1 gene were found in four of the breast tumor cell lines: ZR-75-1, in a dic(8;11); HCC1937, in a t(8;10)(p12;p12.1); SUM-52, in an hsr(8)(p12); UACC-812, in a t(3;8); and in two of the pancreatic cancer cell lines: PaTu I, in a der(8)t(4;8); and SUIT-2, in a del(8)(p). Mapping by two-color FISH showed that the breaks were scattered over 1.1 Mb within the NRG1 gene. It is already known that the MDA-MB-175 breast tumor cell line has a dic(8;11), with a breakpoint in NRG1 that fuses NRG1 to the DOC4 gene on 11q13. Thus, we have found a total of seven breakpoints, in two types of cancer cell lines, that target the NRG1 gene. This suggests that the NRG1 locus is a recurring target of translocations in carcinomas. PCR analysis of reverse-transcribed cell line RNAs revealed an extensive complexity of the NRG1 transcripts but failed to detect a consistent pattern of mRNA isoforms in the cell lines with NRG1 breakpoint

Tomosyn functions as a PKCδ-regulated fusion clamp in mast cell degranulation

International audienceSoluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family proteins mediate membrane fusion critical for vesicular transport and cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the Fcε receptor (FcεRI). We investigated the mechanisms downstream of receptor activation that control degranulation. We found that the SNARE binding protein tomosyn-1 (also known as STXBP5) inhibited FcεRI-stimulated degranulation of mast cells. After mast cell activation, tomosyn-1 was phosphorylated on serine and threonine residues, dissociated from the SNARE protein syntaxin 4 (STX4), and associated with STX3. We identified PKCδ as the major kinase required for tomosyn-1 threonine phosphorylation and for regulation of the interaction with STXs. Incubation with high IgE concentrations increased tomosyn-1 abundance in cultured mast cells. Similarly, in basophils from allergic patients with high amounts of serum IgE, the abundance of tomosyn-1 was increased as compared to that in patients with normal IgE concentrations. Our findings identified tomosyn-1 as an inhibitor of mast cell degranulation that required PKCδ to switch its interaction with STX partners during fusion. We suggest that the IgE-mediated increase in tomosyn-1 abundance in allergic patients may represent a counterregulatory mechanism to limit disease development.Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works