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We report the unusual transformation of a case of Waldenström's macroglobulinemia (WM) into IgM multiple myeloma (MM). The initial clinical and biological presentation of the disease was typical smouldering WM, with lymphocytic infiltration of the bone marrow. Five years later, signs of transformation appeared: the patient presented with diffuse osteolytic bone lesions without organomegaly, and the bone marrow was infiltrated with characteristic malignant plasma cells. Electron microscopy (EM) examination showed that the endoplasmic reticulum (ER) of the dysmorphic plasma cells contained monoclonal IgM. Immunolabeling for calreticulin, a resident protein of the ER, demonstrated unequivocally that the characteristic intranuclear inclusions were indeed part of ER. Flow cytometry revealed an MM profile for the cellular proliferation. Molecular biology performed on the final marrow could only retrieve a single cellular clone. In conclusion, this is the first documented description of the transformation of typical WM into an aggressive form of MM. [ABSTRACT FROM AUTHOR]

Among proteins stored in α-granules, multimerin and factor V share unusual features: they bind to each other, are proteolysed to unique forms and are stored eccentrically in α-granules. These unique features of their processing led us to study these proteins in alpha delta storage pool deficiency (αδ-SPD) and grey platelet syndrome (GPS, α-SPD), two conditions known to impair α-granule protein storage. Platelet factor V and multimerin were severely reduced in GPS, whereas they ranged from reduced to normal in αδ-SPD. The platelet levels of factor V and multimerin in these disorders indicated multimerin deficiency was not predictive of platelet factor V deficiency, although it reduced the amount of multimerin associated with platelet factor V. In GPS only, the defect in storing proteins was associated with increased multimerin and multimerin-factor V complexes in plasma. Like normal platelets, GPS and αδ-SPD platelets contained factor V mainly in granules. Platelet factor V and multimerin were proteolysed to normal platelet forms in GPS and αδ-SPD platelets, indicating that these conditions preserve some aspects of normal α-granule protein processing. Although we found factor V can be stored in platelets deficient in multimerin, our data indicate that multimerin storage influences the point at which multimerin binds factor V. [ABSTRACT FROM AUTHOR]

The αIIbβ3 platelet receptor antagonist abciximab (c7E3Fab, ReoPro®) has proved to be effective in preventing arterial thrombosis. However, its binding capacity to the platelet precursors, megakaryocytes (MKs), which also express αIIbβ3, is not known. The purpose of this study was to establish whether abciximab is able to react with αIIbβ3 located on human MKs, and to follow its subsequent intracellular trafficking. MKs were grown from CD34+ progenitors from normal subjects and from a patient with type I Glanzmann's thrombasthenia, and abciximab was added at day 10 of culture (4 μg/ml). Cells were fixed at day 12, cryosectioned, and immunolabelled for abciximab. Labelling was prominent on the MK plasma membrane; it also lined the demarcation membration system. Interestingly, α-granule membranes were labelled showing that the antibody was internalized and further stored into MK secretory granules. Abciximab was also strongly detected on and in newly-formed platelets. Glanzmann's disease MKs (which completely lacked αIIbβ3) were consistently negative, confirming that the antibody fragment was specifically interacting with αIIbβ3. In conclusion, this study demonstrated that abciximab: (i) binds MK plasma membrane and demarcation membranes, (ii) trafficks into α-granules, and (iii) is expressed on and in nascent platelets. These findings could be taken in account when monitoring anti-αIIbβ3 receptor therapy. [ABSTRACT FROM AUTHOR]

In normal platelet α-granules von Willebrand factor (VWF) is stored with multimerin and factor V in an eccentric electron-lucent zone. Because the platelet stores of VWF are deficient in ‘platelet low’ type 1 and type 3 von Willebrand disease (VWD), we investigated their electron-lucent zone proteins. The patients with VWD had partial to complete deficiencies of plasma and platelet VWF but normal α-granular multimerin and factor V, and normal α-granular fibrinogen, thrombospondin-1, fibronectin, osteonectin and P-selectin. In type 3 VWD platelets, α-granular electron-lucent zones lacking VWF-associated tubules were identified and multimerin was found in its normal α-granular location. These findings indicate that the formation of the electron-lucent zone and the sorting of multimerin to this region occur independent of VWF. The isolated abnormalities in VWF suggests a VWF gene mutation is the cause of ‘platelet low’ type 1 VWD. [ABSTRACT FROM AUTHOR]

Background Information: The identification of a source of stem cells able to regenerate skeletal muscle was the goal of numerous studies with the aim to develop new therapeutic approaches for genetic muscle diseases or muscle injuries. A series of studies have demonstrated that stem cells derived from various tissues may have a role in the regeneration of damaged muscles, but this contribution is always very weak. Thus we established a project aiming to reprogramme non-muscle cells into the skeletal striated differentiation pathway., Results: We transduced several human primary adult stem or progenitor cells using a recombinant lentivirus containing the coding sequence of the Myf5 gene considered as a master gene for the determination of skeletal striated muscle. These original results are the first demonstration of a myogenic conversion of human mesenchymal and endothelial cells by Myf5., Conclusions: The procedure described in the present paper could be used to develop new research protocols with the prospect of using these cells as therapeutic agents.