[Show abstract][Hide abstract] ABSTRACT: Neuroguidin (NGDN) is a eukaryotic translation initiation factor 4E binding protein. The purpose of this study was to clarify the function of NGDN and its possible mechanism of action in human myeloid leukemia cells. Proliferation inhibition and apoptosis in NGDN over-expressing myeloid multidrug-resistant leukemia cells (K562/A02-NGDN) was significantly higher than in control K562/A02 cells following treatment with vincristine, etoposide, and epirubicin, indicating that NGDN over-expression can increase the sensitivity of multidrug-resistant leukemia cells to chemotherapeutic drugs. Furthermore, NGDN knock-down in K562/A02 cells resulted in the activation of multiple tumor-related signaling pathways, especially the mammalian target of rapamycin (mTOR) pathway.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0108-6) contains supplementary material, which is available to authorized users.
Preview · Article · Dec 2015 · Journal of Hematology & Oncology
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3 (MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen (i.e., CD47) and the down-regulation of active antigens (i.e., CD86, CD54, retinoic acid early transcript (RAE), histocompatibility 2, D region locus b (H2-Db) and H2-Dd). Natural killer (NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells.
Full-text · Article · Nov 2015 · Science China. Life sciences
[Show abstract][Hide abstract] ABSTRACT: The fetal liver serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in fetal liver remain poorly understood. In this study, we demonstrate that deletion of the activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in fetal liver. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros (AGM) region was not affected. The migration activity of ATF4(-/-) HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in fetal liver was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed down-regulated expression of a panel of cytokines in ATF4(-/-) stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor-A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4(-/-) HSCs in the culture. Furthermore, ChIP assay in conjunction with siRNA-mediated silencing and cDNA over-expression showed transcriptional control of Angptl3 by ATF4. Taken together, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing fetal liver, and it acts through up-regulating transcription of cytokines such as Angptl3 in the microenvironment.
[Show abstract][Hide abstract] ABSTRACT: The benefit of adjuvant therapy (AT) for gallbladder cancer (GBC) is unclear as evidenced by conflicting results from nonrandomized studies. Here we aimed to perform a meta-analysis to determine the impact of AT on overall survival (OS).
We used data from MEDLINE, EMBASE and the Cochrane Collaboration Library and published between October 1967 and October 2014. Studies that evaluated AT compared with curative-intent surgery alone for resected GBC were included. Subgroup analyses of benefit based on node status, margins status, and American Joint Committee on Cancer (AJCC) staging were prespecified. Data were weighted and pooled using random-effect modeling.
Ten retrospective studies involving 3,191 patients were analyzed. There was a nonsignificant improvement in OS with AT compared with surgery alone (hazard ratio [HR], 0.76; 95 % confidence interval [CI], 0.56-1.03). A significant improvement was observed in OS with chemotherapy (CT) compared with surgery alone (HR, 0.42; 95 % CI, 0.22-0.80) by sensitivity analysis. The greatest benefit for AT was also observed in those with R1 disease (HR, 0.33; 95 % CI, 0.19-0.59), LN-positive disease (HR, 0.71; 95 % CI, 0.63-0.81), and AJCC staging meeting or exceeding tumor Stage II (HR, 0.45; 95 % CI, 0.26-0.79), but not in those with LN-negative or R0 disease.
Our results strongly support the use of CT as an AT in GBC. Moreover, patients with node positivity, margin positivity, or non-stage I disease are more likely to benefit from AT.
[Show abstract][Hide abstract] ABSTRACT: In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCsICOS-EGFP) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSCsICOS-EGFP, MSCs, MSCsEGFP, ICOS-Ig fusion protein, MSCs + ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4+ T-cell apoptosis and proliferation, and Th1/Th2/Th17 effecter cell polarization were evaluated. In the C57BL/6 → CB6F1 HSCT model, the long-term survival in the MSCICOS-EGFP group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p p = 0.004; 48.57 ± 8.45%, p = 0.03; or 50.43 ± 8.45% p = 0.04, respectively). The survival advantages of MSCICOS-EGFP-treated group were confirmed in the C57BL/6 → BALB/c HSCT model. In both HSCT models, the low mortality in the MSCICOS-EGFP group was associated with lower incidence and severity of acute GvHD. Treatment with MSCsICOS-EGFP induced more CD4+ T-cell apoptosis compared with that in the GvHD group. The effect on CD4+ T cells was shown as early as day 2 and maintained until day 14 (p ICOS-EGFP were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-γ, IL-2, IL-12, and IL-17A were detected in the MSCICOS-EGFP group. The MSCsICOS-EGFP could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-γt expression. Our results showed that injection of MSCsICOS-EGFP is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage.
No preview · Article · Sep 2015 · Cell Transplantation
[Show abstract][Hide abstract] ABSTRACT: In clinic settings, rel apsed leukemic patients are found to be more fragile to chemotherapy due to delayed or incomplete hematopoietic recovery, and hematopoiesis of these patients seem to be impaired.
We established a leukemia therapy model with a non-irradiated T cell acute lymphoblastic leukemia mouse model combined with cytarabine and cyclophosphamide. Dynamic kinetics and functional status of both primitive hematopoietic cells and leukemic cells in a leukemia host under the chemotherapy stress were comprehensively investigated.
We successfully established the leukemia therapy model with T lymphoblastic phenotype. After treatment with cytarabine and cyclophosphamide, the frequency of L − K + S + hematopoietic cells tides with the therapy, and stabled when the disease remission, then reduced when relapsed, while leukemic cells showed a delayed but consistent regeneration. Combination of chemotherapy significantly promote an early and transient entrance of L − K + S + hematopoietic cells into active proliferation and induction of apoptosis on L − K + S + cells in vivo. Moreover, in the competitive bone marrow transplantation assays, hematopoietic cells showed gradually diminished regenerative capacity. Testing of senescence-associated beta-galactosidase (SA-β gal) status showed higher levels in L − K + S + hematopoietic cells post therapy when compared with the control. Gene expression analysis of hematopoietic primitive cells revealed up-regulated p16, p21, and down-regulated egr1 and fos.
We conclude that primitive hematopoietic cells in bone marrow enter proliferation earlier than leukemic cells after chemotherapy, and gradually lost their regenerative capacity partly by senescence due to accelerated cycling.
Full-text · Article · Jul 2015 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft‑versus‑host disease (aGVHD). However, the role of MSCs in graft‑versus‑leukemia remains to be determined. In the present study, we co‑cultured C57BL/6 mouse bone marrow (BM)‑derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.
Preview · Article · Apr 2015 · International Journal of Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: To improve the MigR1-CD19-CAR (chimeric antigen receptor) that contains a single chain variable region (scFv) which targeted to CD19 through a retroviral vector transduction efficiency of T-lymphocytes.
Insert the CD19-CAR fragment into the retroviral vector (MigR1) through recombinant DNA technology, after transfecting plat-A packaging cell lines, viral supernatant was collected to transduce K562 cell line and activated human T-lymphocytes. We used flow cytometry to determine the transduction efficiency and RT-PCR to confirm the transcription of CD19-CAR gene. The ability of the transduced T cells to produce IFN-γ and TNF-α in a CD19-specific manner was measured in an enzyme-linked immunosorbent (ELISA) assay.
(1)Using MigR1-CD19-CAR retroviral vector to produce the high titer retrovirus. (2)MigR1-CD19-CAR transduction efficiency of K562 cell line was significantly higher than human T-lymphocytes (P<0.01). (3)120 min centrifugation could significantly improve transduction efficiency of T-lymphocytes to (54.5±14.6)%. (4)Transduction efficiency could be improved by deciding transduce time according to T-lymphocytes proliferation fold in vitro individually, and the highest transduction efficiency in the study was 69.3%. The CD19-CAR gene sequence was transcripted specificly with high efficiency. (5) IFN-γ and TNF-α released by CD19-CAR transduced T-lymphocytes significantly increased to (13 230±1 543) pg/ml and (4 217±211) pg/ml when coculture with CD19-K562 cells.
We have successfully constructed a second generation CAR which targeted to CD19 through a retroviral vector called MigR1 (MigR1-CD19-CAR). Deciding transduce time according to T-lymphocytes proliferation fold in vitro individually and 120 min centrifugation could improve the CAR transduction efficiency of T-lymphocytes. RT-PCR confirmed that the CD19-CAR gene was specificly transcripted with high efficiency. IFN-γ and TNF-α released by CD19-CAR transduced T-lymphocytes significantly increased when activated by target cells.
No preview · Article · Apr 2015 · Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
[Show abstract][Hide abstract] ABSTRACT: Backgrownd: Macrophage inflammatory protein-1α (MIP-l α/CCL3) belongs to the C-C chemokine family (CCL3), which can be secreted by macrophages, other types of hematopoietic cells and bone marrow stromal cells. Higher levels of MIP-1α were found to be associated with several kinds of hematologic malignancies, including multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Moreover, MIP-1α has been reported to be an adverse prognostic factor for CLL. However, the impact of MIP-1α on acute myeloid leukemia (AML) has been poorly investigated.
To investigate the influence of MIP-1α on proliferction of AML cells.
Using MLL-AF9 induced AML mouse model, the expression of MIP-1α was measured by real time quantitative RT-PCR. AML cell proliferation was examined by cell counting and colony forming assay (CFC). The influence of blocking the MIP-1α action on the growth and pathogenic ability of AML cells was explored by using the small molecule antagonist for interfering interaction of MIP-1α with its receptor CCR1.
The MIP-1α could promote the proliferation and colony formation of AML cells, the blocking MIP-1a could inhibit the growth of AML cells and delay onset of AML.
The MIP-1a promotes the occurence and progression of AML, therefore blocking the MIP-1α signal pathway may be served as a strategy to inhibit the growth of AML cells, and MIP-1α can be a potential target for treatment of AML.
No preview · Article · Apr 2015 · Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology
[Show abstract][Hide abstract] ABSTRACT: To explore the effects and possible mechanisms of decitabine on Molt4 in vitro.
Effects of decitabine on cells proliferation were detected by using CCK-8, the apoptosis by Annexin V-FITC, cell cycles by propidium iodide-FACS. Discrepancy genes were screened by RNA-seq technique. The CpG methylation of lactoferrin (LTF) gene in Molt4 cells were identified by Bisulfite sequencing PCR (BSP). The expression of LTF mRNA in Molt4 by RT-PCR and LTF protein expression were analyzed by Western blot.
Decitabine effectively inhibited proliferation and induced apoptosis for Molt4 cells by an time- and dose-dependent manners. Cell cycles were arrested at the G₀/G₁ phase. The promoter methylation degree of LTF gene in Molt4 cells was 72.3% before decitabine treatment and decreased to 45.0% after treatment with 0.50 μmol/L decitabine for 72 h. After the reduction of methylation, expression of its mRNA and protein increased, meanwhile caspase 3 and caspase 9 protein expression levels increased.
The demethylating drug decitabine can induce apoptosis, detain cell cycle at phase G₀/G₁, inhibit proliferation and up-regulate LTF gene expression in Molt4 cells. LTF may become a new target for acute T lymphoblastic leukemia.
No preview · Article · Mar 2015 · Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
[Show abstract][Hide abstract] ABSTRACT: Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel small-molecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.
Full-text · Article · Feb 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: To report an acute promyelocytic leukaemia (APL) case with translocation of rob (13;21) t(15;17)(q22;q21) and review its clinical and laboratory characteristics.
Based on routine karyotype analysis and bone marrow morphology, we further used double color double fluorescent in situ hybridization (DCDF-FISH) and reverse transcriptase PCR (RT-PCR) to examine the patient's abnormities on cytogenetic and molecular biology, and reveal the clinical characteristics of this rare translocation also from the related literatures.
The clinical manifestation and bone marrow morphology examination of this patient were in accordance with pathologic feature of APL. On first visit, immunophenotyping analysis showed positive myeloid markers. Through R-banding, the patient's karyotype was confirmed as 45,XX,rob(13;21)t(15;17)(q22;q21)/45,XX,rob(13;21). FISH results showed that 68.9% cells were typical t(15;17) pattern. The positive rates of fusion gene of PML-RARα detected by RT-PCR was 25.8%. Patient was treated by induction and consolidation therapy, the karyotype was 45,XX,rob(13;21) after complete remission. The positive rate of fusion gene of PML-RARα by FISH and its level were 2.5% and 0.003% respectively.
APL with rob (13;21) t(15;17)(q22;q21) was very rare, which was accorded with clinical and laboratory characteristics of APL. The value of chromosome abnormality as a prognostic marker in APL needs to be further observed..
No preview · Article · Jan 2015 · Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
[Show abstract][Hide abstract] ABSTRACT: To investigate the patients' characteristics and efficacy of prognosis evaluation by International Prognosis Scoring System (IPSS) and Revised International Prognosis Scoring System (IPSS-R) in patients with myelodysplastic syndrome (MDS).
Prognostic value of IPSS and IPSS-R was evaluated on clinical data from 159 MDS patients, according to WHO classification.
With a median age of 44 years (range:15-80 years), MDS patients had the frequency of 38.56% with abnormal karyotype, including the most common abnormality +8 (20/153, 12.6%). 34 of 142 patients transformed into leukemia. Age and the level of β2 micro-globulin were the prognostic factors by multivariate analysis and IPSS-R had a better prognostic significance. The differences in cumulative survival between IPSS subgroups were significant (P<0.05) except that between low- and intermediate I-risk group (P>0.05). There were statistical differences for IPSS-R low risk group vs high or very high risk group, and intermediate risk group vs high or very high risk group (P<0.05). IPSS-R enables IPSS subgroups re-stratification and split IPSS intermediate I-risk group into two subgroups with different prognosis.
There were significant differences in age of onset, distribution of prognosis scoring system subgroups and abnormal karyotype compared with those in Europe and America. The proportion of higher risk (worse than good karyotype) in IPSS-R was higher than that in Europe and America. Age and the level of β2 micro-globulin were prognostic factors. Both IPSS and IPSS-R were applicable in Chinese MDS patients and the latter performed better. Applying IPSS-R to re-stratify IPSS subgroups helps evaluate prognosis more accurately and improve treatment outcomes.
No preview · Article · Dec 2014 · Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
[Show abstract][Hide abstract] ABSTRACT: Background
Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed.MethodsA Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice.ResultsMore leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3ß was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3ß recruits T-ALL cells which express a high level of MIP-3ß receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3ß, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice.Conclusions
Our study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia.
Full-text · Article · Nov 2014 · Journal of Hematology & Oncology
[Show abstract][Hide abstract] ABSTRACT: Immuno-compromised mice, such as the non-obese diabetic/severe combined immune-deficient (NOD/SCID) mice, have been widely used to examine the in vivo self-renewal and differentiation of human hematopoietic stem cells (HSCs). However, the efficiency of human HSC engraftment remains very low. Here, we report that NOD/SCID mice had higher levels of reactive oxygen species (ROS) in their bone marrow (BM) than other commonly used mouse strains (C57BL/6 and BALB/C). Treatment with the antioxidant N-acetyl-L-cysteine (NAC) decreased ROS levels in the BM of NOD/SCID mice. Furthermore, the NAC-treated mice displayed a significant increase in human HSC engraftment and multi-lineage differentiation compared with the controls. In comparison with the control mice, NAC-treated recipients displayed a 10.8-fold increase in engraftment in the injected tibiae. A beneficial effect of NAC for human hematopoietic engraftment was also observed in an additional immune-deficient mouse strain, namely NOD.Cg-Prkdc(scid)I12rg(tm1Wjl)/SzJ (NOD/SCID/γc(-/-) or NSG). Therefore, our current study uncovers a previously unappreciated negative effect of ROS on human stem cell engraftment in immune-deficient mouse models.
[Show abstract][Hide abstract] ABSTRACT: Acute graft-versus-host disease (aGvHD) is the most common complication of allogeneic hematopoietic stem cell transplantation (HSCT), which is often accompanied by impaired hematopoietic reconstitution. Sinusoidal endothelial cells (SECs) constitute bone marrow (BM) vascular niche that plays an important role in supporting self-renewal capacity and maintaining the stability of HSC pool. Here we provide evidences that vascular niche is a target of aGvHD in a major histocompatibility complex (MHC)-haploidentical matched murine HSCT model. The results demonstrated that hematopoietic cells derived from GvHD mice had the capacity to reconstitute hematopoiesis in healthy recipient mice. However, hematopoietic cells from healthy donor mice failed to reconstitute hematopoiesis in GvHD recipient mice, indicating that the BM niche was impaired by aGvHD in this model. We further demonstrated that SECs were markedly reduced in the BM of aGvHD mice. High level of Fas and caspase-3 expression and high rate of apoptosis were identified in SECs, indicating that SECs were destroyed by aGvHD in this murine HSCT model. Furthermore, high Fas ligand expression on engrafted donor CD4+, but not CD8+ T cells, and high level MHC-II but not MHC-I expression on SECs, suggested that SECs apoptosis was mediated by CD4+ donor T cells through the Fas/FasL pathway.
[Show abstract][Hide abstract] ABSTRACT: Cytopenia and delayed immune reconstitution with acute graft-versus-host disease (aGvHD) indicate a poor prognosis. However, how donor-derived cell hematopoiesis is impaired in aGvHD is not well understood. We addressed this issue by studying the kinetics of hematopoiesis and the functions of hematopoietic stem and progenitor cells (HSPCs) in an aGvHD model with haplo-MHC-matched murine bone marrow transplantation (BMT). Although hematopoiesis was progressively suppressed during aGvHD, the hematopoietic regenerative potential of donor-derived HSCs remains intact. There was a dramatic reduction in primitive hematopoietic cells and a defect in the ability of these cells to generate common myeloid progenitors (CMPs) and megakaryocyte/erythrocyte progenitors (MEPs). These effects were observed along with a concomitant increase in granulocyte/macrophage progenitors (GMPs), suggesting that differentiation into MEPs is blocked during aGvHD. Interestingly, cyclosporine A (CsA) was able to partially reverse the hematopoietic suppression as well as the differentiation blockage of CMPs. These data provide new insights into the pathogenesis of aGvHD and may improve the clinical management of aGvHD.
Full-text · Article · May 2014 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation