Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis

ABSTRACT GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.

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SCL/TAL1 Regulates Erythropoietin Receptor Expression.

Blood ◽

10.1182/blood.v108.11.1195.1195 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1195-1195

Author(s):

Heather M. Rogers ◽

Xiaobing Yu ◽

Constance Tom Noguchi

Keyword(s):

Erythroid Differentiation ◽

Erythropoietin Receptor ◽

Receptor Expression ◽

Binding Motif ◽

Erythroid Cells ◽

Hematopoietic Stem ◽

Mild Anemia ◽

Adult Mice ◽

High Level

Abstract The basic-helix-loop-helix transcription factor SCL/TAL1, is required for erythropoiesis during development, and conditional deletion in adult hematopoiesis results in hematopoietic stem cells with a competitive repopulation disadvantage and defective erythropoiesis in vitro. However, adult mice with a conditional SCL/TAL1 deletion survive with mild anemia, suggesting defective erythroid proliferation and indicating that SCL/TAL1 is important, but not essential in mature red blood cell production. We find that during erythroid differentiation of primary human hematopoietic CD34+ cells, SCL/TAL1 expression peaks at day 8–10 following erythropoietin (EPO) stimulation, concomitant with peak expression of GATA-1 and EKLF. Treatment with SCL/TAL1 antisense oligonucleotides during erythroid differentiation markedly decreases erythroid differentiation as indicated by decreased expression of GATA-1 and both b- and g-globin expression, along with the absence of the characteristic decrease in GATA-2. Microarray analysis of erythroid cells overexpressing SCL/TAL1 indicate increased gene expression for b- and g-globin, and other genes related to erythropoiesis including EPO receptor (EPO-R), and these results are confirmed in stable cell lines with increasing SCL/TAL1 expression. Examination of EPO-R transcription regulation indicates that E-boxes in the 5′ UTR can bind SCL/TAL1 in vitro and, in addition to the GATA-1 binding motif, provide transcription activity in reporter gene assays. These data indicate that in addition to the importance of SCL/TAL1 DNA binding for proliferation of BFU-E and expression of glycophorin A and protein 4.2, SCL/TAL1 is also necessary for high level expression of EPO-R. Reduction in EPO-R expression likely contributes to the anemia associated with the conditional adult deletion of SCL/TAL1 and to the proliferative defect of erythroid cells observed in vitro. Early expression of SCL/TAL1 in hematopoietic cells may activate expression of EPO-R prior to EPO stimulation of erythropoiesis and induction of GATA-1.

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Reciprocal Activation of GATA-1 and PU.1 Marks Initial Specification of Hematopoietic Stem Cells into Myelo-Erythroid and Myelo-Lymphoid Lineages.

Blood ◽

10.1182/blood.v110.11.1228.1228 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1228-1228

Author(s):

Yojiro Arinobu ◽

Shin-ichi Mizuno ◽

Yong Chong ◽

Hirokazu Shigematsu ◽

Tadafumi Iino ◽

...

Keyword(s):

Cell Biology ◽

Erythroid Differentiation ◽

Self Renewal ◽

Hematopoietic Stem ◽

Loss Of Self ◽

Hematopoietic Lineage ◽

Multipotent Progenitors ◽

High Resolution Map ◽

Fate Decision ◽

High Level

Abstract Understanding how multipotent cells commit to each of their terminal fate potentials is an important aspect of stem cell biology. In adult murine hematopoiesis, HSCs with long-term self-renewal potential reside within the Lin −Sca-1+c-Kit+ (LSK) fraction having CD34−, Thy1lo, and Flt3/Flk2−phenotypes. The LSK cells having CD34+, Thy1−, and/or Flt3+ phenotypes are capable of multi-lineage reconstitution only for a short-term, and therefore should contain multipotent progenitors (MPPs). In terms of developmental steps downstream of MPPs, there has been a controversy. The existence of prospectively isolatable progenitors capable of generating only myeloerythroid cells (common myeloid progenitor: CMP) or only lymphocytes (common lymphoid progenitors: CLP) outside the LSK fraction suggests that the first commitment step after the MPP stage is the strict bifurcation of lymphoid vs. myeloid pathway. Recently, however, several studies have suggested that the lineage commitment could occur within the LSK fraction, preceding the proposed bifurcation of myeloid and lymphoid pathways. For example, MPPs expressing Flt3 at a high level retained granulocytes/monocytes (GM) but not megakaryocyte/erythrocyte (MegE) potential together with lymphoid potential, suggesting the existence of common progenitor for GM and lymphoid lineages within the LSK fraction. Based on this data, the coupled loss of self-renewal activity and MegE potential in the early HSC commitment has been proposed. How can we reconcile the controversy in the early hematopoietic lineage map? By utilizing mice having GATA-1 or PU.1 transcriptional reporters, we here present a high-resolution map containing new lineage-restricted progenitor populations within the MPP population of CD34+ LSK phenotype. Initial upregulation of GATA-1 and PU.1 occurred independently at the MPP stage. The GATA-1+ MPP displayed potent myeloerythroid potential without giving rise to lymphocytes, whereas the PU.1+ MPP showed granulocyte/monocyte/lymphoid-restricted progenitor activity without megakaryocyte/erythroid differentiation. Furthermore, GATA-1+ and PU.1+ MPPs possessed huge expansion potential, and differentiated into the original CMPs and CLPs, respectively. Thus, the reciprocal activation of GATA-1 and PU.1 primarily organizes hematopoietic lineage fate decision to form the earliest hematopoietic branchpoint that comprises new, isolatable myeloerythroid and myelolymphoid progenitor populations.

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GATA2 Zinc Finger Mutations Influence Erythroid Differentiation and Chemotherapy Response

Blood ◽

10.1182/blood-2019-128218 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1459-1459

Author(s):

Georg Leubolt ◽

Enric Redondo Monte ◽

Anja Wilding ◽

Paul Kerbs ◽

Monica Cusan ◽

...

Keyword(s):

Zinc Finger ◽

Research Funding ◽

Blast Crisis ◽

K562 Cells ◽

Erythroid Differentiation ◽

Therapy Resistance ◽

Chemotherapy Response ◽

Dependent Manner ◽

Monocytic Differentiation ◽

Hematopoietic Stem

The transcription factor GATA2 plays an important role in cell lineage decisions during hematopoiesis. GATA2 Zinc-Finger (ZF) mutations are associated with distinct entities of myeloid malignancies. Alterations of the N-terminal ZF1 were identified in AML patients with biallelic CEBPA mutations, whereas the C-terminal ZF2 is typically affected by germline mutations predisposing to MDS and AML, or by somatic lesions in CML blast crisis. Nevertheless, the context-dependent mechanisms underlying GATA2 ZF mutations remain mostly unclear. Here, we set out to study the functional consequences of GATA2 ZF mutations. To test the effect on differentiation, we expressed GATA2 wild-type (WT) or GATA2 ZF mutants in human CD34+ hematopoietic stem and progenitor cells, stimulated with appropriate cytokines. Differentiation was evaluated by FACS-measurements of surface marker expression (erythroid markers: CD71, CD235a; granulocytic/monocytic markers: CD15, CD14). GATA2 WT caused a block of erythroid differentiation that is overcome by the ZF1 mutants (A318T and G320D), whereas the ZF2 mutant L359V may aggravate this block. For granulocytic/monocytic differentiation an overall block was observed for GATA2 WT and all the ZF mutants tested (Figure 1 A, B). Recently, we and others observed GATA2 mutation gain in AML relapse (Greif et al., 2018 Clin Cancer Res; Christopher et al., 2018, NEJM), pointing towards a potential role in therapy resistance. Therefore, we treated K562 cells stably expressing GATA2 WT or mutants with Daunorubicin (one of the two drugs commonly used in AML chemotherapy). Expression of GATA2 A318T in K562 cells correlated with higher sensitivity to Daunorubicin and lower expression levels of IDH2. (Figure 1 C, D). Interestingly, this particular ZF1 mutation was the only one that got lost at relapse in the study by Christopher and colleagues, consistent with therapy sensitivity, whereas most of the GATA2 mutations gained at relapse were localized in the ZF2 domain. In summary, GATA2 ZF mutations influence hematopoietic differentiation and chemotherapy response in a position-dependent manner. In the present study, we report distinct roles for individual GATA2 mutations depending on the affected ZF domain and altered amino acid positions. Understanding the oncogenic collaboration of GATA2 mutations with other driver genes in distinct patient subgroups is a challenge ahead. Figure.1 Disclosures Hiddemann: Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding.

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Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells

Journal of Experimental Medicine ◽

10.1084/jem.20062395 ◽

2007 ◽

Vol 204 (7) ◽

pp. 1603-1611 ◽

Cited By ~ 73

Author(s):

Cindy G. Leung ◽

Yanfei Xu ◽

Bretton Mularski ◽

Hui Liu ◽

Sandeep Gurbuxani ◽

...

Keyword(s):

Steady State ◽

Spindle Assembly Checkpoint ◽

Survivin Expression ◽

Erythroid Differentiation ◽

Inhibitor Of Apoptosis ◽

Specific Gene ◽

Erythroid Cells ◽

Hematopoietic Stem ◽

Apoptosis Protein ◽

High Level

Survivin, which is the smallest member of the inhibitor of apoptosis protein (IAP) family, is a chromosomal passenger protein that mediates the spindle assembly checkpoint and cytokinesis, and also functions as an inhibitor of apoptosis. Frequently overexpressed in human cancers and not expressed in most adult tissues, survivin has been proposed as an attractive target for anticancer therapies and, in some cases, has even been touted as a cancer-specific gene. Survivin is, however, expressed in proliferating adult cells, including human hematopoietic stem cells, T-lymphocytes, and erythroid cells throughout their maturation. Therefore, it is unclear how survivin-targeted anticancer therapies would impact steady-state blood development. To address this question, we used a conditional gene-targeting strategy and abolished survivin expression from the hematopoietic compartment of mice. We show that inducible deletion of survivin leads to ablation of the bone marrow, with widespread loss of hematopoietic progenitors and rapid mortality. Surprisingly, heterozygous deletion of survivin causes defects in erythropoiesis in a subset of the animals, with a dramatic reduction in enucleated erythrocytes and the presence of immature megaloblastic erythroblasts. Our studies demonstrate that survivin is essential for steady-state hematopoiesis and survival of the adult, and further, that a high level of survivin expression is critical for proper erythroid differentiation.

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Inhibition of Human Erythropoiesis during Inflammation Is Mediated By High Mobility Group Box Protein 1 (HMGB1) through Decreased Commitment of Hematopoietic Stem Cells to the Erythroid Lineage and By Increased Apoptosis of Terminally Differentiating Erythroblasts

Blood ◽

10.1182/blood.v128.22.702.702 ◽

2016 ◽

Vol 128 (22) ◽

pp. 702-702

Author(s):

Brian M. Dulmovits ◽

Julien Papoin ◽

John Hale ◽

Jian Hua Li ◽

Huan Yang ◽

...

Keyword(s):

Culture System ◽

Inflammatory Diseases ◽

High Mobility ◽

Erythroid Differentiation ◽

Erythroid Cell ◽

Dependent Manner ◽

Erythroid Progenitors ◽

Monocytic Cells ◽

Hematopoietic Stem ◽

Sepsis Survivors

Abstract Anemia plays a significant role in the morbidity and mortality of chronic inflammatory diseases and post-sepsis recovery. Inflammation-associated anemia is further complicated as these conditions are typically refractory to erythropoietin (EPO) administration, which suggests that circulating inflammatory molecules prevent effective erythropoiesis. High mobility group box protein 1 (HMGB1), a pro-inflammatory molecule involved in sepsis has been shown to mediate anemia in a murine model of sepsis survivors. However, the effects of soluble HMGB1 on human erythropoiesis remain poorly understood. To address this issue, we studied the effect of increasing concentrations of HMGB1 on human erythropoiesis in vitro using CD34+ hematopoietic stem and progenitor cells (CB HSPCs) and a previously described 3-phase erythroid differentiation culture system to asses the effects on erythroid cell proliferation as well as the semisolid methylcellulose assay to study effects on erythroid progenitors. HMGB1 markedly reduced erythroid cell proliferation in the 3-phase culture system in a dose-dependent manner. We evaluated the contributions of early- and late-stage erythropoiesis to decreased erythroid proliferation using using flow cytometric analyses of cell surface markers interleukin-3 receptor (IL-3R), glycophorin A (GPA), CD36, CD34 (BFU-E and CFU-E) and GPA, α4-integrin and band 3 (ProEB-orthoEB). HMGB1 increased the percentage of IL-3Rpos cells (vehicle v HMGB1: 8.6% vs 15.5%), and reduced the percentage of GPApos cells (vehicle v HMGB1: 32.2% v 12.8%) implying decreased commitment of CB HSPCs to erythroid lineage in the presence of HMGB1. Flow cytometric analysis confirmed an increased commitment to myeloid lineage and Giemsa-stained cytospins revealed increased numbers of myelo-monocytic cells in HMGB1 cultures. Furthermore, the decreased number of erythroid progenitors generated in culture was blocked in terminal differentiation leading to increased apoptosis of erythroblasts. Since we found increased numbers of myelo-monocytic cells and increased erythroblast apoptosis in HMGB1 treated cultures, we performed additional studies to investigate the role of soluble HMGB1 on HSPC lineage commitment and erythroblast survival signaling (i.e. EPO signaling). CB CD34+ HSPCs were seeded in fully enriched methylcellulose ± HMGB1, and hematopoietic colony numbers were quantified based on morphologic characteristics. HMGB1 increased the number of CFU-GM colonies and decreased the number of erythroid colonies (CFU-E, BFU-E). Further, erythroblasts treated with 3IU/mL EPO ± HMGB1 revealed that HMGB1 significantly reduced EPO-dependent STAT5 phosphorylation in a dose-dependent manner. In order to begin to identify the HMGB1 receptors responsible for HSPC lineage skewing and erythroblast apoptosis we used transcriptome-wide RNA-sequencing data to examine the expression patterns of various HMGB1 receptors during differentiation of HSPCs in our culture system. Toll-like receptor 2 (TLR2), TLR4 and CXCR4 are expressed during the early-stages of erythroid differentiation while the receptor for advanced glycation end products (RAGE) is expressed only during late stages of erythroid differentiation. These findings suggest that two discrete HMGB1-receptor signaling axes may underlie the noted changes in early- and late-stage cellular differentiation in our culture system. Taken together, our results identify HMGB1 as a potent inhibitor of human erythropoiesis. HMGB1 exerts this effect at two levels of erythroid differentiation, the first during the commitment of HSPC to erythroid differentiation and subsequently during terminal erythroid differentiation. The erythroid differentiation defect appears to be partially dependent on EPO signaling while it has no effect on the HSPC defect. We proposed that the elevated HMGB1 during inflammation could explain the persistent erythroid defect observed in patients with chronic inflammatory diseases and sepsis survivors. Disclosures No relevant conflicts of interest to declare.

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Regulatory Reprogramming of Erythropoiesis By DNMT3A Mutation

Blood ◽

10.1182/blood-2018-99-120110 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4343-4343

Author(s):

Janghee Woo ◽

Sandra Stehling-Sun ◽

H. Joachim Deeg ◽

Thalia Papayannopoulou ◽

Fyodor D Urnov ◽

...

Keyword(s):

Dna Methyltransferase ◽

Catalytic Domain ◽

Conflicts Of Interest ◽

Erythroid Differentiation ◽

Regulatory Elements ◽

Rna Seq ◽

Hematopoietic Stem ◽

Regulatory Landscapes

Abstract DNA methyltransferase 3A (DNMT3A) regulates diverse epigenetic processes, and DNMT3A mutations occur frequently in myelodysplastic syndromes (MDS), including in founding clones of MDS samples. Most DNMT3A mutations affect Arg882 (R882) in the catalytic domain of DNMT3A, and are found almost exclusively in a heterozygous state. To resolve the relationship between the genetic and epigenetic architectures of R882H+ MDS, we engineered primary human CD34+ hematopoietic stem and progenitor cells (HSPCs) to carry heterozygous DNMT3A R882H and performed temporally resolved, genome-wide regulatory mapping via DNase-seq combined with RNA-seq during erythroid differentiation in vitro, and in an in vivo transplantation model. Compared with isogenic controls, heterozygous R882H HSPCs cells exhibited markedly impaired erythroid differentiation, accumulation of early myeloid progenitors, and diverse maturation defects. Transplantation of R882H HSPCs into W41 NSG mice revealed both impaired erythroid differentiation and preferential survival of mutant alleles in multiple hematopoietic lineages compatible with an early progenitor defect. Regulatory profiling of DNMT3A R882H heterozygous cells during differentiation via combined DNase- and RNA-seq revealed global and sequential alterations in the regulatory landscapes in mutant cells, most prominently decommissioning of thousands of regulatory regions normally found in primitive cells that mark gene loci destined for expression during later differentiation stages. Decommissioned regulatory elements in R882H heterozygotes were concentrated around genes involved in both regulation of erythropoiesis and cell-cycle control, biasing HSPC differentiation away from erythropoiesis. Similar findings were observed in CD34+-selected bone marrows from 33 patients with MDS, comparing heterozygous DNMT3A R882H and wild type. Collectively, our results indicate that DNMT3A R882H mutation reprograms early myeloid regulatory landscapes by preferentially targeting elements that control genes destined to be expressed at later stages of differentiation, resulting in a combined phenotype of impaired myeloid differentiation, impaired erythroid maturation, and preferential survival of R882H+ cells. The results provide novel mechanistic insights into the chromatin programming of erythroid differentiation and its connection with MDS. Disclosures No relevant conflicts of interest to declare.

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A Modular Enhancer Is Differentially Regulated by GATA and NFAT Elements That Direct Different Tissue-Specific Patterns of Nucleosome Positioning and Inducible Chromatin Remodeling

Molecular and Cellular Biology ◽

10.1128/mcb.02323-06 ◽

2007 ◽

Vol 27 (8) ◽

pp. 2870-2885 ◽

Cited By ~ 36

Author(s):

Andrew G. Bert ◽

Brett V. Johnson ◽

Euan W. Baxter ◽

Peter N. Cockerill

Keyword(s):

T Cells ◽

Mast Cells ◽

Myeloid Cells ◽

Cell Types ◽

Dependent Manner ◽

Tissue Specific ◽

Gm Csf ◽

Gata Factors ◽

Gene Enhancer ◽

High Level

ABSTRACT We investigated alternate mechanisms employed by enhancers to position and remodel nucleosomes and activate tissue-specific genes in divergent cell types. We demonstrated that the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene enhancer is modular and recruits different sets of transcription factors in T cells and myeloid cells. The enhancer recruited distinct inducible tissue-specific enhanceosome-like complexes and directed nucleosomes to different positions in these cell types. In undifferentiated T cells, the enhancer was activated by inducible binding of two NFAT/AP-1 complexes which disrupted two specifically positioned nucleosomes (N1 and N2). In myeloid cells, the enhancer was remodeled by GATA factors which constitutively displaced an upstream nucleosome (N0) and cooperated with inducible AP-1 elements to activate transcription. In mast cells, which express both GATA-2 and NFAT, these two pathways combined to activate the enhancer and generate high-level gene expression. At least 5 kb of the GM-CSF locus was organized as an array of nucleosomes with fixed positions, but the enhancer adopted different nucleosome positions in T cells and mast cells. Furthermore, nucleosomes located between the enhancer and promoter were mobilized upon activation in an enhancer-dependent manner. These studies reveal that distinct tissue-specific mechanisms can be used either alternately or in combination to activate the same enhancer.

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High-level correction of the sickle mutation amplified in vivo during erythroid differentiation

10.1101/432716 ◽

2018 ◽

Cited By ~ 6

Author(s):

Wendy Magis ◽

Mark A. DeWitt ◽

Stacia K. Wyman ◽

Jonathan T. Vu ◽

Seok-Jin Heo ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Genetic Disorders ◽

Erythroid Differentiation ◽

Hematopoietic Stem ◽

Curative Therapy ◽

Human Hscs ◽

High Level

ABSTRACTSickle Cell Disease (SCD), one of the world’s most common genetic disorders, causes anemia and progressive multiorgan damage that typically shortens lifespan by decades; currently there is no broadly applicable curative therapy. Here we show that Cas9 RNP-mediated gene editing with an ssDNA oligonucleotide donor yields markerless correction of the sickle mutation in more than 30% of long-term engrafting human hematopoietic stem cells (HSCs), using a selection-free protocol that is directly applicable to a clinical setting. We further find that in vivo erythroid differentiation markedly enriches for corrected ß-globin alleles. Adoption of a high-fidelity Cas9 variant demonstrates that this approach can yield efficient editing with almost no off-target events. These findings indicate that the sickle mutation can be corrected in human HSCs at curative levels with a streamlined protocol that is ready to be translated into a therapy.ONE SENTENCE SUMMARYCas9-mediated correction of the sickle mutation in human hematopoietic stem cells can be accomplished at curative levels.

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Decrease post-transplant relapse using donor-derived expanded NK-cells

Leukemia ◽

10.1038/s41375-021-01349-4 ◽

2021 ◽

Author(s):

Stefan O. Ciurea ◽

Piyanuch Kongtim ◽

Doris Soebbing ◽

Prashant Trikha ◽

Gregory Behbehani ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Ex Vivo ◽

Disease Free Survival ◽

Dependent Manner ◽

Post Transplant ◽

Haploidentical Transplantation ◽

High Doses ◽

High Level

AbstractIn this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105–1 × 108 cells/kg/dose) were administered on days −2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 (https://clinicaltrials.gov/ct2/show/NCT01904136).

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