A germ line mutation in cathepsin B points toward a role in asparaginase pharmacokinetics.

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment. (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Amyloidosis is a heterogeneous group of diseases, in which amyloidogenic precursor proteins misfold and adopt a b-pleated sheet conformation. 1 Several proteins can form amyloid fibrils in vivo including transthyretin, 2 apolipoprotein A-I and A-II, lyso-zyme, fibrinogen, serum amyloid A protein and immunoglobulin light chains, but " cross-fibril " seeding appears to be rare such that 2 types of amyloid are rarely identified in the same individual. 3 Congo red (CR) staining with apple green birefringence under polarized light is used to confirm the presence of amyloid, 4 whereas immunohis-tochemistry, staining the biopsy tissue with a panel of monospecific antibodies against known amyloidogenic proteins, is the technique most widely used to characterize the amyloid fibril protein, but it is flawed. 5 Proteomic analysis involves proteolytic cleavage of proteins within microdissected amyloidotic tissue and identification by mass spectometry. 6 This additional tool is being increasingly used in conjunction with immunohistochemistry to identify the amyloid fibril protein. We describe a case in which 2 amyloid fibril proteins were isolated in an individual patient both by immunohistochemistry and by proteomic analysis. An 81-year-old man was referred to our center with a 6-to 7-month history of exertional dyspnea and New York Heart Association class II symptoms. Baseline investigations included an echocardiogram showing characteristic features of cardiac amyloid-osis with a thickened interventricular wall of 18 mm, moderate di-astolic dysfunction, and preserved left ventricular ejection fraction of 58% accompanied by elevated serum cardiac biomarkers (N-terminal fragment brain natriuretic peptide 1966 ng/L and troponin T 0.09 mg/mL). 123 I-labeled serum amyloid P component scintigraphy did not show visceral amyloid deposits, 7 but 99m Tc-dicarboxypropane diphosphonate (99m Tc-DPD) scintigraphy showed abnormal (Perugini grade 2) cardiac uptake, typical of cardiac transthyretin amyloidosis 8 and unusual in light chain (AL) amyloidosis. 9 The k-serum free light chain concentration was 13.1 mg/L, l was 644 mg/L, and l BJP was present. A bone marrow biopsy showed 6% plasma cells and immunophenotyping isolated a CD19 2 , CD56 1 , CD27 1 plasma cell clone. Sequencing of the transthyretin gene was wild-type. The differential diagnosis was between wild-type cardiac transthyretin (ATTR) amyloidosis (senile systemic amyloidosis) …