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Inside the May and June 2013 Issues

Posted By Connections Editor, Sunday, June 30, 2013
Updated: Friday, June 28, 2013

Take a quick tour of the May and June issues and get a feel for the publication's cutting-edge scientific content. Read the full issues online.

In this Issue – May 2013

#Migration of hematopoietic precursors during development and its clinical implications
Ciriza et al.

Fetal hematopoietic stem cells (HSCs) need to migrate through different niches located in diverse anatomic microenvironments to gain the necessary molecule repertoire to engraft and home into the bone marrow. This review by Ciriza etal. comprehensively summarizes early and recent work related to multipotential cells in the yolk sac, placenta, intraembryonic sites including the AGM and the fetal liver, as well as factors that affect interaction of these cells with the local microenvironment. These factors include a host of adhesion molecules, chemokines, cytokines, and ECM molecules, which are discussed in much detail and without significant bias in a presentation of opposing models. The authors also devote a significant amount of discussion to the important issue of embryonic stem cell differentiation into transplantable, long-term self-renewing HSCs, and they propose intriguing ideas for why this process might not be efficient. This timely review is highly relevant to readers looking to further their understanding of fetal HSC migration and of the potential application of that knowledge to stem cell and transplantation biology.

#A step further toward the generation of a viable in-vitro stem cell niche
Deneault et al.

The importance of extrinsic regulation of hematopoietic stem cell (HSC) activity is increasingly acknowledged. Invivo, the stem cell niche integrates a complex mixture of different cells and signaling molecules. This microenvironment is not easily imitable invitro, making it difficult to maintain HSC activity in culture for extended periods of time. In this study, Deneault etal. engineered niche cells to overexpress several nuclear factors agonists of HSC activity, which they identified in a previous report. They find that most of the tested intrinsic factors have actually a non–cell autonomous effect on HSC activity. In addition, they explore the transcriptional regulatory networks that have been rewired within engineered niche cells. Interestingly, the identification of the involvement of FOS, SPI1, KLF10, TFEC, and PRDM16, which consistently interact epistatically, reveal a novel non–cell autonomous network in engineered niche cells that support HSC activity. Moreover, these five factors are normally involved in osteoclastogenesis invivo, supporting the hypothesis that osteoclasts might also be part of the functional HSC niche. Finally, the authors uncover an important contrast between mouse and human HSC biology, because the engineered niches failed to enhance activity of human HSCs, as opposed to mouse HSCs. This finding suggests that HSC self-renewal determinants are poorly conserved between the two species. These findings contribute to characterize the functional niche that supports HSC activity and pave the way for the identification of new secreted growth factors that expand HSC numbers in culture to improve transplantation-based therapies.

#The hematopoietic role of the sodium-dependent phosphate import protein Sodium-Dependent Phosphate Import Protein, PiT1, is not associated with phosphate transport
Liu et al.

Emerging data suggest that the sodium-dependent phosphate import protein, PiT1 (SLC20A1), modulates cellular proliferation. In this article, Liu L. etal. characterize the hematopoietic phenotype of mice with conditional deletion of Pit1 and show that the animals develop a severe macrocytic anemia with a block in terminal erythroid differentiation around the proerythroblast stage. The mice also have a profound B cell deficiency, which primarily reflects a block at the pro-B stage in development, mild neutropenia, and thrombocytopenia. Importantly, the mice have a general hematopoietic cell defect in cell cycle progression in the absence of a change in cellular phosphate uptake, consistent with a phosphate import–independent role for PiT1 in governing cellular proliferation. This work contributes to the currently limited published data on the role of metabolite transporters in hematopoiesis and raises the intriguing possibility that PiT1 could have separable phosphate transport and cellular proliferation signaling functions. Moreover, as the hematopoietic phenotype of Pit1-deleted mice shares several features with low-grade myelodysplastic syndrome (MDS), and MDS is associated with Gibbon Ape leukemia virus and feline leukemia virus B infections (both utilize PiT1 for cell entry) in nonhuman primates and cats, respectively, future studies of these Pit1-deleted mice and PiT1-associated pathways could also provide insight into the pathobiology of these disorders.

#KI haplotype A: A novel predictive factor of complete molecular response in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors
La Nasa et al.

Growing evidence suggests that the occurrence of chronic myeloid leukemia (CML), the disease course, and the response of patients to therapy with tyrosine kinase inhibitors can be influenced by inhibitory and activating receptors regulating the function of natural killer (NK) cells. NK cells are important mediators of both innate and adaptive immune responses. NK cell recognition and lysis of tumor cells is regulated by the interaction of killer cell immunoglobulin-like receptors (KIRs) expressed on the NK cell surface and human leukocyte antigen (HLA) class I alleles expressed on target cells. It is speculated that changes in the balance of inhibitory and activating KIR signals could lead to NK cell deficiency, contributing to the occurrence of CML and hampering patients’ response to treatment. In this study by La Nasa etal., the authors present a retrospective study of KIR profiles and response to therapy in an ethnically and genetically homogeneous cohort of CML patients and control subjects. They show that patients homozygous for the KIR haplotype A have a significantly higher probability of achieving early and sustained complete molecular response (CMR) than do patients with AB or BB genotypes. Achievement of CMR is also associated with a reduced frequency of KIR2DL2 and a low number of inhibitory KIR genes. Considering that group A haplotypes have only six inhibitory genes and that KIR2DL2 is exclusively carried by group B haplotypes, it is possible that the KIR haplotype AA could represent a valuable marker of durable CMR. The identification of such markers, combined with the currently known prognostic factors for CMR, should help clinicians make informed decisions regarding the modulation and possible withdrawal of tyrosine kinase inhibitor treatment in patients with CML.

In this Issue – June 2013

#A mouse model of Hoxa9-mediated pre-T Lymphoblastic Leukemia
Beachy et al.

Despite the strong association of Hoxa9 expression with T cell and myeloid leukemia, enforced expression of Hoxa9 in murine bone marrow or thymus has only modest malignant transforming abilities. To gain a better understanding of the relationship between Hoxa9 overexpression and hematopoietic malignancies, Beachy etal. generated transgenic mice that ectopically expressed Hoxa9, by targeting transgene expression to hematopoietic tissues with Vav regulatory elements. When studying four lines of Hoxa9 transgenic mice from different potential founders, two major findings were observed. First, overexpression of the Hoxa9 transgene was associated with embryonic lethality, as two of the four potential founders did not transmit the transgene to surviving offspring, but analysis of embryos from timed pregnancies indicated that the embryos were viable until at least E9.5. Second and somewhat unexpected, a fraction of viable Hoxa9 mice developed pre-T lymphoblastic leukemia (LBL) or lymphoma, all with Notch1 mutations, but none of the mice developed acute myeloid leukemia (AML). Notably, Hoxa9 mice with pre-T LBL lacked global upregulation of other Hoxa cluster genes or mir-196b, which expression has been shown to be increased in other genetically engineered mice that express leukemic fusion genes (e.g., MLL-AF9, CALM-AF10, NUP98-HOXD13). Interestingly, Hoxa9 bone marrow could be immortalized invitro with the addition of Meis1, suggesting that lack of Meis1 overexpression in the Hoxa9 mice might partially explain why AML was not observed in this study. The authors propose that this Hoxa9 transgenic mouse might be a useful tool for studying collaborative events needed for the development of pre-T LBL or AML.

#Increased sensitivity of acute myeloid leukemia CD34+ cells to bortezomib by targeting NF-κB and MCL-1
Bosman et al.

Despite treatment with intensive chemotherapy, many patients with acute myeloid leukemia (AML) still have unfavorable outcomes. Various innovative therapeutic options have been explored to target the small population of leukemic stem cells that is responsible for the development of leukemia and relapse after treatment. Constitutive activation of NF-κB has been observed in AML blasts, and proteasome inhibition, which results in degradation of NF-κB, has been suggested to specifically induce apoptosis in AML CD34+/CD38 cells. Clinical studies evaluating the effect of the proteasome inhibitor bortezomib in patients with AML have been initiated. However, the efficacy of bortezomib in targeting AML stem cells has not been investigated thoroughly. This article by Bosman etal. provides evidence that the leukemic stem cell–enriched CD34+ fraction is resistant to bortezomib, using invitro stem cells assays on CD34+ samples from patients with AML. Interestingly, bortezomib resistance in CD34+ AML cells was largely dependent on inadequate inhibition of NF-κB, which might be related to differences in NF-κB activation in AML CD34+ versus CD34 cells. Intriguingly, proteasome inhibition resulted in the upregulation of the important antiapoptotic protein MCL-1. Inhibition of MCL-1 strongly increased the sensitivity of AML CD34+ cells to bortezomib. Future research should therefore be focused on combining bortezomib with MCL-1 inhibitors for the treatment of patients with AML. Furthermore, it will be important to evaluate whether the second-generation proteasome inhibitors that bind the proteasome in an irreversible manner, such as carfilzomib and oprozomib, can, in contrast to bortezomib, reduce the frequency of AML stem cells as single agents.

#Cytokine-induced killer cells as therapy against multiple myeloma
Liu et al.

Multiple myeloma (MM) remains an incurable plasma cell malignancy, and innovative therapeutic approaches are urgently needed. In addition to small molecules, immunotherapy using adoptively transferred immune cells, cancer vaccines, and virotherapy using tumor-selective oncolytic viruses are being pursued in clinical trials. This study by Liu etal. explores the potential of cytokine-induced killer (CIK) cells as therapy against MM. CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes that present phenotypic and functional properties of both natural killer and T cells, and have major histocompatibility complex–unrestricted antitumor activity against both solid tumors and hematologic malignancies. The authors show that allogeneic CIK cells have antitumor activity against subcutaneous and disseminated animal models of human myeloma (KAS-6/1). The antimyeloma activity of CIK cells can be further enhanced by pretreating the myeloma cells with ionizing radiation or by loading CIK cells with a virotherapy agent—an oncolytic measles virus (MV) that is currently in phase I clinical testing in patients with relapsed or refractory myeloma. Irradiation of the myeloma cells enhanced the delivery of CIK to the irradiated tumors and induced mRNA and protein expression of natural killer group 2 D (NKG2D) ligands, which mediate the antitumor activity of CIK cells. CIK cells can also serve as carriers to protect and deliver the oncolytic virus to tumors to initiate viral induced oncolysis, resulting in superior antitumor activity. This study demonstrates the potential of CIK against MM, and that combination of virotherapy with radiation could be used to enhance therapeutic outcome using CIK cells. CIK therapy is already a clinical reality; therefore, the clinical translation of this promising delivery platform is highly feasible and worth pursuing in future studies.

#Narrowing down the origin of endogenic mesoderm
Kataoka et al.

Hematopoietic precursor cells (HPCs) develop from hemogenic endothelial cells (EC), a specialized type of ECs undergoing hematopoietic transition. Despite their importance, the origin of hemogenic ECs has not been defined clearly. Ets variant 2 (Etv2)/ER71 is a master regulator generating ECs/HPCs from mesoderm. Etv2 deficiency causes complete EC or HPC loss in mouse embryos and differentiated ES cells. In this study by Kataoka etal., the authors tested regional deletion of Etv2 to narrow the critical mesoderm subset that gives rise to hemogenic ECs. They report that among region-specific Cre deleters, Etv2 ablations by Hoxb6 Cre and CreER revealed that caudal-lateral mesoderm including allantois is a critical mesoderm source of intraembryonic hematopoiesis. Explant cultures before hematopoietic cells circulate showed that Etv2 deletion in Hoxb6+ E7.5–8.5 mesoderm causes severe intraembryonic hematopoietic defect with intact yolk sac hematopoiesis. Etv2 deletion in that area also resulted in significant reduction in intraaortic c-Kit+ clusters and umbilical cord Runx1+ cells. Labeling of the relevant population in differentiated ES cells (Flk-1+/Hoxb6+ cells) showed that those cells have hemogenic characteristics over Hoxb6 negative population, including T lymphocyte generation. These findings suggest that Hoxb6+ mesoderm will be a promising source for inducing definitive hematopoietic cells in developing embryos and invitro–differentiated embryonic stem cells. Currently, conventional hematopoietic differentiation methods are failing to efficiently generate Hoxb6+/Flk-1+ cells. Future efforts are necessary to optimize the culture condition for efficiently inducing Hoxb6+ mesoderm

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