👤 Lucienne Michaux

Myeloid/Lymphoid Neoplasms with eosinophilia and involvement of Tyrosine Kinase gene fusions (MLN-TK) is a WHO disease category including a diverse group of malignancies characterised by recurrent genomic rearrangements of tyrosine kinase (TK) genes such as PDGFRA, PDGFRB, FGFR1, JAK2, ETV6 and FLT3. Identification of these TK rearrangements is important for the accurate diagnosis of MLN-TK and allows targeted therapy with TK inhibitors. In this study, we validated the use of optical genome mapping (OGM) retrospectively by analysing 11 samples from 10 cases with suspected or known TK rearrangements, previously analysed by current standard of care (SOC) methodologies, i.e., chromosome banding analysis (CBA), FISH and/or PCR-based techniques. In six abnormal cases, OGM was able to detect the rearrangements previously determined by SOC methods. Furthermore, OGM identified the fusion partner in the JAK2- and PDGFRB-rearranged cases and elucidated the mechanism underlying the BCR::FGFR1 and ETV6::SYK rearrangement. In two cases with a normal karyotype, OGM detected two cryptic FIP1L1::PDGFRA and TNIP1::PDGFRB rearrangements. In the two remaining cases, no abnormalities were detected either by OGM or SOC methods. We demonstrate that OGM is a valid technique for the diagnostic workflow of MLN-TK, able to detect TK rearrangements and to identify unknown TK fusion partners. Show less

Myeloid sarcoma (MS), previously known as granulocytic sarcoma or chloroma, is a rare neoplastic condition defined as a tumor mass consisting of myeloblasts or immature myeloid cells occurring at an extramedullary site. Clinical presentation is diverse and determined by a tumor mass effect or local organ dysfunction. We report the case of a 25-year-old previously healthy male with rapidly progressive shortness of breath. A chest CT scan demonstrated a heterogenous anterosuperior mediastinal mass with pleural and pericardial invasion. A diagnosis of MS with both myeloid and lymphoid characteristics was made by pathologic, morphologic, and immunophenotypic investigation. Next generation analysis revealed a pathogenic TP53 mutation (c.1035₁₀₃₆insCT, p.Glu346Leufs*25). After 4 cycles of chemotherapy only a partial metabolic response and tumor size reduction was obtained. A pretransplant bone marrow biopsy revealed the progression of disease to acute myeloid leukemia. Cytogenetic analysis demonstrated a t(10; 11)(p12;q21). Fluorescence in situ hybridization confirmed the presence of a PICALM-MLLT10 fusion gene. MS with a mediastinal localization is rare and often misdiagnosed as malignant lymphoma. Acute leukemia harboring a PICALM-MLLT10 fusion gene is characterized by a mixed T cell and myeloid phenotype. The rearrangement is a rare recurrent translocation associated with specific clinical features, as illustrated in this case report. Show less

The neuronal ceroid lipofuscinoses (NCLs) are severe inherited neurodegenerative disorders affecting children. In this disease, lysosomes accumulate autofluorescent storage material and there is death of neurons. Five types of NCL are caused by mutations in lysosomal proteins (CTSD, CLN1/PPT1, CLN2/TTPI, CLN3 and CLN5), and one type is caused by mutations in a protein that recycles between the ER and ERGIC (CLN8). The CLN6 gene underlying a variant of late infantile NCL (vLINCL) was recently identified. It encodes a novel 311 amino acid transmembrane protein. Antisera raised against CLN6 peptides detected a protein of 30 kDa by Western blotting of human cells, which was missing in cells from some CLN6 deficient patients. Using immunofluorescence microscopy, CLN6 was shown to reside in the endoplasmic reticulum (ER). CLN6 protein tagged with GFP at the C-terminus and expressed in HEK293 cells was also found within the ER. Investigation of the effect of five CLN6 disease mutations that affect single amino acids showed that the mutant proteins were retained in the ER. These data suggest that CLN6 is an ER resident protein, the activity of which, despite this location, must contribute to lysosomal function. Show less