Experimental Hematology RSS feed: Current Issue. Initial review of manuscripts averages under 4 weeks Articles published online from 5 days after acceptance Unrivalled access to 10 million healthcare professionals through ScienceDirect Over 280,000 article downloads in 2012 Impact factor of 2.905 (© Thomson Reuters Journal Citation Reports 2012) Experimental Hematology publishes original research reports (regular and fast-track submissions ), reviews, perspectives, letters to the editor, and abstracts of the annual meeting of ISEH - Society for Hematology and Stem Cells . We welcome manuscripts describing basic in vitro and in vivo research centered on normal and malignant hematopoiesis as well as non-malignant hematologic diseases. Submissions focused on non-hematopoietic stem cells (e.g. mesenchymal stem cells, embryonic stem cells and induced pluripotent stems) with potential relevance to hematopoiesis are also welcome, as are studies involving experimental or early phase clinical cell transplantation. Studies employing genomic and systems biology approaches to the study of normal and malignant hematopoiesis are strongly encouraged, as are those employing model organisms. Benefits to authors We also provide many author benefits, such as free PDFs, a liberal copyright policy, special discounts on Elsevier publications and much more. Please click here for more information on our author services . Please see our Guide for Authors for information on article submission. If you require any further information or help, please visit our support pages: http://support.elsevier.com http://www.exphem.org/?rss=yesElsevier Inc.en © 2013 Published by Elsevier Inc. All rights reserved. Experimental Hematology0301-472X415May 2013 © 2013 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.exphem.org/article/PIIS0301472X1300115X/abstract?rss=yes See Ciriza et al., pages 411–423.Inside this issue10.1016/j.exphem.2013.03.006Experimental Hematology 41, 5 (2013)2013-04-12Experimental Hematology2013-04-12415S0301-472X(13)X0004-9Inside This Issue409410http://www.exphem.org/article/PIIS0301472X13000131/abstract?rss=yesThe ontogeny of hematopoietic stem cells (HSCs) is complex, with multiple sites of embryonic origin as well as several locations of expansion and maturation in the embryo and the adult. Hematopoietic progenitors (HPs) with diverse developmental potential are first found in the yolk sac, aorta-gonad-mesonephros region and placenta. These progenitors then colonize the fetal liver (FL), where they undergo expansion and maturation. HSCs from the FL colonize the fetal bone marrow (FBM), governed by a complex orchestration of transcription programs including migratory molecules with chemotactic activity, adhesion molecules, and molecules that modulate the extracellular matrix. Understanding the mechanisms that regulate the patterns of HSC migration between FL and FBM could improve the engraftment potential of embryonic stem cell–derived HPs, because these cells might display a migratory behavior more similar to early HPs than to adult HSCs. Understanding the changes in migratory behavior in the context of FL to FBM HSC migration could lead to new approaches in the treatment of blood malignancies. We will review the current knowledge in the field of FL to the FBM HSCs migration during development, focusing on changes in expression of molecules important for this process and exploring its clinical applications.The migration of hematopoietic progenitors from the fetal liver to the fetal bone marrow: Lessons learned and possible clinical applicationsJesús Ciriza, Heather Thompson, Raffi Petrosian, Jennifer O. Manilay, Marcos E. García-Ojeda10.1016/j.exphem.2013.01.009Experimental Hematology 41, 5 (2013)2013-02-08Experimental Hematology2013-02-08415S0301-472X(13)X0004-9Review411423http://www.exphem.org/article/PIIS0301472X13000118/abstract?rss=yesSeveral recent reports suggest a possible role for killer immunoglobulin-like receptors (KIR) in the onset of chronic myeloid leukemia (CML) and response to therapy with tyrosine kinase inhibitors (TKIs). To explore this hypothesis, we studied KIRs and their human leukocyte antigen class I ligands in 59 consecutive patients with chronic-phase CML (mean age, 53 years; range, 23–81 years) and a group of 121 healthy control participants belonging to the same ethnic group as the patients. The 2-year cumulative incidence of complete molecular response, obtained after a median of 27 months (range, 4–52 months), was 51.2%. An increased frequency of the activating receptor KIR2DS1 (pm = 0.05) and a reduced frequency of the KIR-ligand combination KIR2DS2/2DL2 absent/C1 present (pm = 0.001) were significantly associated with CML. Moreover, KIR repertoires in patients appeared to influence response to TKI therapy. Homozygosity for KIR haplotype A (pm = 0.01), a decreased frequency of the inhibitory KIR gene KIR2DL2 (pm = 0.02), and low numbers of inhibitory KIR genes (pm = 0.05) were all significantly associated with achievement of complete molecular remission. These data suggest that a decrease in properly stimulated and activated NK cells might contribute to the occurrence of CML and indicate homozygosity for KIR haplotype A as a promising immunogenetic marker of complete molecular response that could help clinicians decide whether to withdraw treatment in patients with CML.Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patientsGiorgio La Nasa, Giovanni Caocci, Roberto Littera, Sandra Atzeni, Adriana Vacca, Olga Mulas, Marzia Langiu, Marianna Greco, Sandro Orrù, Nicola Orrù, Andrea Floris, Carlo Carcassi10.1016/j.exphem.2013.01.008Experimental Hematology 41, 5 (2013)2013-02-04Experimental Hematology2013-02-04415S0301-472X(13)X0004-9Malignant Hematopoesis424431http://www.exphem.org/article/PIIS0301472X13000052/abstract?rss=yesPhosphate is critical in multiple biological processes (phosphorylation reactions, ATP production, and DNA structure and synthesis). It remains unclear how individual cells initially sense changes in phosphate availability and the cellular consequences of these changes. PiT1 (or SLC20A1) is a constitutively expressed, high-affinity sodium-dependent phosphate import protein. In vitro data suggest that PiT1 serves a direct role in mediating cellular proliferation; its role in vivo is unclear. We have discovered that mice lacking PiT1 develop a profound underproduction anemia characterized by mild macrocytosis, dyserythropoiesis, increased apoptosis, and a near complete block in terminal erythroid differentiation. In addition, the animals are severely B cell lymphopenic because of a defect in pro–B cell development and mildly neutropenic. The phenotype is intrinsic to the hematopoietic system, is associated with a defect in cell cycle progression, and occurs in the absence of changes in serum phosphate or calcium concentrations and independently of a change in cellular phosphate uptake. The severity of the anemia and block in terminal erythroid differentiation and B cell lymphopenia are striking and suggest that PiT1 serves a fundamental and nonredundant role in murine terminal erythroid differentiation and B cell development. Intriguingly, as the anemia mimics the ineffective erythropoiesis in some low-grade human myelodysplastic syndromes, this murine model might also provide pathologic insight into these disorders.Mice lacking the sodium-dependent phosphate import protein, PiT1 (SLC20A1), have a severe defect in terminal erythroid differentiation and early B cell developmentLi Liu, Marilyn Sánchez-Bonilla, Matthew Crouthamel, Cecilia Giachelli, Siobán Keel10.1016/j.exphem.2013.01.004Experimental Hematology 41, 5 (2013)2013-02-01Experimental Hematology2013-02-01415S0301-472X(13)X0004-9Malignant Hematopoesis432443.e7http://www.exphem.org/article/PIIS0301472X13000106/abstract?rss=yesAutotaxin (ATX) has been reported to act as a motility and growth factor in a variety of cancer cells. The ATX protein acts as a secreted lysophospholipase D by converting lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which signals via G-protein–coupled receptors and has important functions in cell migration and proliferation. This study demonstrates that ATX expression is specifically upregulated and functionally active in acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) mutation of the FLT3 receptor gene.Moreover, ATX expression was also found in normal human CD34+ progenitor cells and selected myeloid and lymphoid subpopulations. Enforced expression of mutant FLT3-ITD by retroviral vector transduction increased ATX mRNA in selected cell lines, whereas inhibition of FLT3-ITD signaling by sublethal doses of PKC412 or SU5614 led to a significant downregulation of ATX mRNA and protein levels. In the presence of LPC, ATX expression significantly increased proliferation. LPA induced proliferation, regardless of ATX expression, and induced chemotaxis in all tested human leukemic cell lines and human CD34+ progenitors. LPC increased chemotaxis only in cells with high expression of endogenous ATX by at least 80%, demonstrating the autocrine action of ATX. Inhibition of ATX using a small molecule inhibitor selectively induced killing of ATX-expressing cell lines and reduced motility in these cells. Our data suggest that the production of bioactive LPA through ATX is involved in controlling proliferation and migration during hematopoiesis and that deregulation of ATX contributes to the pathogenesis of AML.Autotaxin is expressed in FLT3-ITD positive acute myeloid leukemia and hematopoietic stem cells and promotes cell migration and proliferationClaudia Ortlepp, Christine Steudel, Caroline Heiderich, Sina Koch, Angela Jacobi, Martin Ryser, Sebastian Brenner, Martin Bornhäuser, Benedikt Brors, Wolf-Karsten Hofmann, Gerhard Ehninger, Christian Thiede10.1016/j.exphem.2013.01.007Experimental Hematology 41, 5 (2013)2013-02-01Experimental Hematology2013-02-01415S0301-472X(13)X0004-9Malignant Hematopoesis444461.e4http://www.exphem.org/article/PIIS0301472X1300012X/abstract?rss=yesChronic myelogenous leukemia (CML) is a stem cell disorder, and leukemia stem cells (LSCs) can contribute to the relapse of the disease. Quiescent LSCs are BCR-ABL independent and resistant to imatinib; therefore, there is an unmet need to identify new therapeutic targets in LSCs. Inhibition of the mammalian target of rapamycin (mTOR) in imatinib-resistant BCR-ABL1–positive cells was effective in vitro, but in a pilot clinical trial, only a few patients responded to the treatment. In this study, we demonstrate that mTOR activation in CML CD34+ progenitor cells is ERK dependent in chronic phase of the disease and ERK independent in blast crisis. Rapamycin effectively inhibits mTOR in all phases of CML, but does not reduce number of LSC-enriched CD34+ blast crisis (BC) cells, neither alone nor in combination with imatinib in CML-BC cells. These results show that potential therapeutic benefits of mTOR inhibition may be the result of effects on differentiated leukemic cells and may be potentially achieved only in the chronic phase of the disease.Diverse mechanisms of mTOR activation in chronic and blastic phase of chronic myelogenous leukemiaTomasz Stoklosa, Eliza Glodkowska-Mrowka, Grazyna Hoser, Magdalena Kielak, Ilona Seferynska, Pawel Wlodarski10.1016/j.exphem.2013.02.001Experimental Hematology 41, 5 (2013)2013-02-07Experimental Hematology2013-02-07415S0301-472X(13)X0004-9Malignant Hematopoesis462469http://www.exphem.org/article/PIIS0301472X13000040/abstract?rss=yesIn a previous gain-of-function screen, we identified 18 nuclear factors that enhance mouse hematopoietic stem cell (HSC) activity in vitro. Of these factors, the majority was believed to augment HSC function intrinsically. In the current study, we investigated the mechanisms of action of the previously identified agonists of HSC activity and tested whether human HSCs are also responsive to these factors. Our results unexpectedly revealed that the majority of the identified factors confer a competitive advantage to mouse HSCs in a non–cell-autonomous manner. Five of these factors, namely FOS, SPI1, KLF10, TFEC, and PRDM16, show robust transcriptional cross-regulation and are often associated with osteoclastogenesis. These findings define at least one novel non–cell-autonomous network in engineered niches. Surprisingly, and in contrast to their important effect on mouse HSCs, all engineered niches failed to significantly enhance the activity of human HSCs. This last finding further supports a lack of conservation in determinants that control HSC self-renewal in mouse versus human cells.Identification of non–cell-autonomous networks from engineered feeder cells that enhance murine hematopoietic stem cell activityEric Deneault, Brian T. Wilhelm, Anne Bergeron, Frédéric Barabé, Guy Sauvageau10.1016/j.exphem.2013.01.003Experimental Hematology 41, 5 (2013)2013-01-21Experimental Hematology2013-01-21415S0301-472X(13)X0004-9Microenvironment and Niche470478.e4http://www.exphem.org/article/PIIS0301472X13000167/abstract?rss=yesWe have developed a coculture system that establishes DLK+ fetal hepatic progenitors as the authentic supportive cells for expansion of hematopoietic stem (HSCs) and progenitor cells. In 1-week cultures supplemented with serum and supportive cytokines, both cocultured DLK+ fetal hepatic progenitors and their conditioned medium supported rapid expansion of hematopoietic progenitors and a small increase in HSC numbers. In 2- and 3-week cultures DLK+ cells, but not their conditioned medium, continuously and significantly (>20-fold) expanded both hematopoietic stem and progenitor cells. Physical contact between HSCs and DLK+ cells was crucial to maintaining this long-term expansion. Similar HSC expansion (approximately sevenfold) was achieved in cocultures using a serum-free, low cytokine- containing medium. In contrast, DLK− cells are incapable of expanding hematopoietic cells, demonstrating that hepatic progenitors are the principle supportive cells for HSC expansion in the fetal liver.Fetal hepatic progenitors support long-term expansion of hematopoietic stem cellsSong Chou, Johan Flygare, Harvey F. Lodish10.1016/j.exphem.2013.02.003Experimental Hematology 41, 5 (2013)2013-02-15Experimental Hematology2013-02-15415S0301-472X(13)X0004-9New Techniques and Technologies479490.e4http://www.exphem.org/article/PIIS0301472X13000064/abstract?rss=yesSmall molecule inhibitors of Janus kinase (JAK) family members (JAK1, JAK2, JAK3, and Tyk2) are currently being pursued as potential new modes of therapy for a variety of diseases, including the inhibition of JAK2 for the treatment of myeloproliferative disorders. Selective inhibition within the JAK family can be beneficial in avoiding undesirable side effects (e.g., immunosuppression) caused by parallel inhibition of other JAK members. In an effort to design an assay paradigm for the development of JAK2 selective inhibitors, we investigated whether compound selectivity differed between cellular and purified enzyme environments. A set of JAK2 inhibitors was tested in a high-throughput JAK family cell assay suite and in corresponding purified enzyme assays. The high-throughput JAK cell assay suite comprises Ba/F3 cells individually expressing translocated ETS leukemia (TEL) fusions of each JAK family member (TEL-JAK Ba/F3) and an AlphaScreen phosphorylated-STAT5 (pSTAT5) immunoassay. Compound potencies from the TEL-JAK Ba/F3 pSTAT5 assays were similar to those determined in downstream cell proliferation measurements and more physiologically relevant cytokine-induced pSTAT5 PBMC assays. However, compound selectivity data between cell and purified enzyme assays were discrepant because of different potency shifts between cell and purified enzyme values for each JAK family member. For any JAK small molecule development program, our results suggest that relying solely on enzyme potency and selectivity data may be misleading. Adopting the high-throughput TEL-JAK Ba/F3 pSTAT5 cell assay suite in lead development paradigms should provide a more meaningful understanding of selectivity and facilitate the development of more selective JAK inhibitors.Differential selectivity of JAK2 inhibitors in enzymatic and cellular settingsVioleta Yu, Jeanne Pistillo, Ivonne Archibeque, Josie Han Lee, Bee-Chun Sun, Laurie B. Schenkel, Stephanie Geuns-Meyer, Liqin Liu, Renee Emkey10.1016/j.exphem.2013.01.005Experimental Hematology 41, 5 (2013)2013-01-21Experimental Hematology2013-01-21415S0301-472X(13)X0004-9New Techniques and Technologies491500