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Inside Experimental Hematology: July 2015

Posted By Connections Editor, Monday, August 31, 2015
Updated: Tuesday, August 25, 2015

Current state of attempts to improve the efficacy of cord blood transplantation using stem cell-based technologies
Pineault et al., pages 498–513.


It is increasingly difficult to find suitablematched donors for hematopoietic stem cell transplant in developed countries due to a variety of factors including an aging population and decreased birth rates. Cord blood (CB) stem cells now represent an important source of hematopoietic stem and progenitor cells (HSPC) for patients with no suitable unrelated donor. However, the major limitation of CB transplantation is the limited number of total nucleated cells and HSPCs banked per unit. Transplantation of two partially matched units can overcome this shortcoming but fails to accelerate engraftment. Ex vivo expansion of CB HSPCs has made significant headway in recent years; accelerated neutrophil recovery, improved platelet engraftment, and superior therapeutic outcomes have now been reported in several clinical trials. In this review, Pineault et al. describe some of the most significant advances made toward improving CB engraftment through stem cell engineering. This review focuses on the development of culture strategies designed to expand human HSPCs ex vivo and the enhancement of engraftment through improved homing. The contributions of coculture, cytokines, developmental-related genes, and small molecules to advancements in CB transplantation are discussed. The major findings of studies that defined the short- and long-term engraftment properties of expanded HSPCs are presented in a series of supporting tables. Finally, the results and principal lessons learned from clinical trials conducted with expanded CB HSPCs are presented along with future perspectives of interest. In summary, this review provides experienced or entry-level readers of all fields with an up-to-date assessment of both fundamental and translational research on stem cell–based technologies developed to improve CB transplantation outcomes.

 

A widely applicable Kit and Sca-1 independent identification of hematopoietic stem cells
Vazquez et al., pages 578–585.


Hematopoietic stem cell (HSC) transplantation holds promise in many disease settings, including cancers, bone marrow failure, and autoimmune disease. The surface markers Kit and Sca-1 are commonly used to isolate HSCs in mice. However, some strains of mice, including the NOD mouse that is used to study autoimmune diabetes, do not express Sca-1 on their hematopoietic progenitors. Similarly, Kit is dynamically regulated in response to bone marrow injury and cannot be used to identify HSC following irradiation. It is therefore important to have an alternative identification approach to Kit and Sca-1 staining that is both simple and efficient. In this manuscript, Vazquez et al. found that antibodies to CD201 and CD27 enable HSC identification across a wide variety of mouse strains, and the expression of these markers is maintained following irradiation. These markers will facilitate the application of HSC transplantation to disease models such as the NOD mouse, as well as in settings where Kit and Sca-1 are dynamically regulated.

 

Proapoptotic function of hyperactivated AKT1 in AML
Tang et al., pages 554–564.


Elevated levels of phosphorylated AKT1 are frequently seen in leukemic blast cells. However, reoccurring mutations in the Akt1 gene are absent in patients with acute myeloid leukemia (AML), raising the question whether permanent AKT1 activation is incompatible with leukemogenesis. Previous reports have indicated that AKT1 activation leads to increased levels of reactive oxygen species (ROS), triggering apoptosis. Whether this is true in cells coexpressing other genetic events in leukemia is not known. To elucidate whether AKT1 causes apoptosis when coexpressed with additional oncogenes seen in AML, in this study, Tang et al. coexpressed hyperactivated AKT1 with STAT5, FLT3-ITD, or antiapoptotic Bcl-2 in hematopoietic progenitors. Hyperactivation of AKT1 was incompatible with both STAT5- and FLT3-ITD-driven proliferation, and triggered cell cycle block and apoptosis. Moreover, transplantable cells of Bcl-2 transgenic mice were impaired in their engraftment ability when expressing hyperactivated AKT1. Cells expressing hyperactivated AKT1 displayed higher levels of ROS, which could be counteracted by addition of the antioxidant N-acetyl-L-cysteine (NAC). These results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML. Because the harmful effects of hyperactivated AKT1 on hematopoietic cells was linked to an improper balance of ROS, this could be one reason why activating mutations of Akt1 are absent in AML. Considering that activating mutations of FLT3-ITD and other signaling proteins in leukemia activate the PI3K/AKT pathway, future drug development to enhance AKT1 activity could lead to novel ways of eradicating leukemic cells.

 

LSD-1 inhibitor RN-1 induces γ-globin expression in a sickle mouse model
Rivers et al., pages 546–553.


Increased fetal hemoglobin production is associated with decreased symptoms and increased life span in patients with sickle cell disease (SCD). Lysine demethylase-1 (LSD1), an enzyme that removes methyl groups from mono- and dimethylated lysine 4 amino acids of histone H3, is a repressor of γ-globin gene expression. LSD1 is also highly overexpressed in many cancers and is a target for anticancer drug therapies. Tranylcypromine (TCP), an FDA-approved LSD-1 inhibitor, increases γ-globin in cultured human erythroid progenitors and induces differentiation of AML cell lines in combination with retinoic acid. Using a novel approach, in this manuscript, Rivers et al. identified RN-1 as a biologically active LSD-1 inhibitor that induced differentiation of the U937 AML cell line with increased potency compared to tranylcypromine. The authors then performed in vivo studies in the SCD mouse model to test the ability of this drug to induce γ-globin messenger RNA. RN-1 treatment of SCD mice induced γ-globin messenger RNA, F cells, and F retics to higher levels than either TCP or hydroxyurea, and its effect was comparable to decitabine, currently in clinical trials for SCD. Because the level of γ-globin induction in the SCD mouse model is low, the authors intend to perform additional studies in the baboon nonhuman primate model that has reproducibly facilitated clinical translation of novel fetal hemoglobin–inducing therapies for SCD.

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