ABSTRACT
Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.
Subject(s)
Blood Platelet Disorders/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , cdc25 Phosphatases/genetics , Animals , Blood Platelet Disorders/complications , Blood Platelet Disorders/pathology , Cell Cycle/genetics , Cell Line , Core Binding Factor Alpha 2 Subunit/genetics , DNA Damage , GATA2 Transcription Factor/genetics , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Pedigree , Thrombocytopenia/genetics , cdc25 Phosphatases/metabolismABSTRACT
Mucosa-associated lymphoid tissue (MALT) lymphoma usually arises from chronic inflammation. We herein report a case of small intestinal MALT lymphoma with protein-losing enteropathy (PLE). A 73-year-old woman presented with lower leg edema and severe hypoalbuminemia. She had a medical history of pylorus-preserving pancreaticoduodenectomy with Billroth II reconstruction. Oral and anal route double-balloon enteroscopies revealed irregular nodular mucosal lesions with erosion extending from the jejunum to terminal ileum. Histopathological evaluation of the biopsied mucosa showed proliferation of small-to-medium-sized lambda light chain-restricted B cells. Plasmacytic differentiation and lymphoepithelial lesions were present, leading to the diagnosis of MALT lymphoma. Tc-99m albumin scintigraphy indicated tracer exudation in the small bowel, suggesting the presence of PLE. Combination immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen improved both MALT lymphoma and PLE, whereas rituximab monotherapy was not successful. This case is considered to be common type of MALT lymphoma at an uncommon site and is distinct from immunoproliferative small intestinal disease (IPSID). To our knowledge, this is the first case of non-IPSID-type small intestinal MALT lymphoma complicated by PLE. Gastrointestinal reconstruction may be responsible for underlying chronic inflammation via small intestinal bacterial overgrowth.
