Most human cancers including myeloma are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human pre-neoplastic and malignant plasma cells together with non-malignant cells in vivo [?]. Growth was largely restricted to the bone marrow, mirroring the pattern in patients. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes. Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors [?].
Sphingosine 1-phosphate guides the elongation of megakaryocytic proplatelet extensions and triggers their shedding.
• Sphk2 provides a source of intracellular S1P that tightly controls thrombopoiesis by regulating SFK expression and activity in MKs.• Modulation of intracellular S1P by regulating Sphk2 may provide a new strategy to enhance platelet production in patients with thrombocytopenia.Human megakaryocytes (MKs) release trillions of platelets each day into the circulation to maintain normal homeostatic platelet levels. We have previously shown that extracellular sphingosine 1-phosphate (S1P) plays a key role in thrombopoiesis via its receptor S1pr1. In addition to its role as an extracellular mediator, S1P can also function as a second messenger in the intracellular compartment. Although signaling via intracellular S1P is involved in various cellular processes, a role in thrombopoiesis has not been examined. Sphingosine kinases are the key enzymes that produce intracellular S1P. Here we report that sphingosine kinase 2 (Sphk2) is the major messenger RNA species present in MKs. Sphk2 predominantly localizes to the nucleus and is the major source of intracellular S1P in MKs. Loss of Sphk2 significantly reduced intracellular S1P in MKs and downregulated the expression and activity of Src family kinases (SFKs). Loss of Sphk2 and inhibition of SFK activity resulted in defective intravascular proplatelet shedding, the final stage of thrombopoiesis. Correspondingly, mice lacking Sphk2 in the hematopoietic system display thrombocytopenia. Together, our data suggest that Sphk2 provides the source of intracellular S1P that controls thrombopoiesis, which is associated with SFK expression and activity in MKs. (Blood. 2013;122(5):791-802) IntroductionThe presence of sufficient numbers of functional platelets in the blood is critical for proper hemostasis. Platelets (150 3 10 9 /L to 400 3 10 9 /L) circulate in normal human blood with a short life span (5-9 days). 1To maintain a normal number of platelets in the circulation, it is estimated that the platelet precursor cells, megakaryocytes (MKs), release 15 3 10 9 to 40 3 10 9 platelets each day. However, MKs are an extremely rare cell population in bone marrow (BM) (,0.01% of BM cells), indicating that each MK has to produce 1000 to 3000 platelets during its lifetime.2 To efficiently release platelets into the circulation, MKs strategically locate close to BM sinusoids and protrude long cytoplasmic extensions through the endothelium into the sinusoidal lumen. The long cytoplasmic processes extending from MKs are termed proplatelets (PPs). 4 PPs consist of multiple platelet-sized beads connected by cytoplasmic bridges. Previous investigations have shown that platelets are released from the tips of PPs 4 and that microtubule and cortical forces regulate terminal platelet size.5 However, little is known about the molecular mechanisms that control the release of platelets from MKs.Sphingosine 1-phosphate (S1P) is an important bioactive lipid with pleiotropic cellular functions. 6 We have shown recently that extracellular S1P serves as a critical directional cue guiding the elongation o...
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