Acquired immune thrombotic thrombocytopenic purpura (TTP) associated with inactivated COVID-19 vaccine CoronaVac.

Corona virus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the whole world. Acquired thrombotic thrombocytopenic purpura (TTP) has been reported after administration of mRNA- or adenoviral vector-based COVID-19 vaccines, including Ad26.COV2-S, BNT162b2, mRNA-1273, and ChAdOx1 nCov-19. However, whether inactivated vaccines, such as CoronaVac, could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown. In this study, two cases were reported. Both cases developed TTP after the second CoronaVac vaccination shot, but not the first. They demonstrated symptoms of fever, neurological abnormalities, renal dysfunction, thrombocytopenia, and hemolysis. Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression. The incidence of TTP in Nanjing area was analyzed. The number of patients with TTP was 12 in 2019, 6 in 2020, 16 in 2021, and 19 in 2022. To the authors' knowledge, this report is the first report of TTP associated with inactivated COVID-19 vaccine (CoronaVac). The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones. Timely plasma exchange is a vital treatment for CoronaVac-related TTP, similar to activated vaccine-related TTP.

Diagnosis, treatment and genetic analysis of an elderly patient with Gaucher's disease characterized by marked multiple bone destruction.

Gaucher's disease is a rare autosomal recessive genetic disease. Due to the decrease or lack of glucocerebrosidase (GBA) activity in lysosome caused by the mutation of GBA gene, its substrate glucocerebroside is detained in lysosome, resulting in clinical manifestations of liver, spleen, kidney, bone, hematopoietic system and even nervous system involvement. Here, we report a case of elderly patient presenting marked multiple bone destruction, with childhood medical history of splenectomy and "osteomyelitis". The patient has a significantly enlarged liver, accompanied by anemia, thrombocytopenia and osteopenia. Laboratory studies show this patient has low blood GBA activity and high glucosyl sphingosine level and increased chitotriosidase activity. Genetic testing revealed a homozygous missense variant NM_001005741.2 c.770A>G (p.Asp257Gly) in the patient's GBA gene. After 6 months of enzyme replacement therapy, the patient's platelets returned to normal, anemia improved, and liver volume decreased. Further detections show that the mother and brothers of the patient have heterozygous mutations at this locus, which is consistent with Mendelian inheritance law. Although this variant has not been reported in literatures or database, both clinical manifestations, characteristics of enzymology and biomarkers, and the effect of enzyme replacement therapy support the diagnosis of Gaucher's disease. The Asp257Gly variant is therefore assessed as a clinical pathogenic variant. This study expands the spectrum of the GBA gene variants. The diagnosis and treatment process of this case also provide reference for the early identification, diagnosis and early treatment of this kind of patients.

Specific overexpression of SIRT1 in mesenchymal stem cells rescues hematopoiesis niche in BMI1 knockout mice through promoting CXCL12 expression.

Osteoblastic lineage cells (OBCs) are bone-building cells and essential component of hematopoietic niche, but mechanisms whereby bone-building and hematopoiesis-supportive activities of OBCs could be regulated simultaneously remain largely unknown. Here we found that B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) was involved in such a co-regulatory mechanism. In this study, we first found that, accompanied with marked decline of osteogenic activity, the hematopoietic niche in Bmi1 knockout (KO) mice was severely impaired and manifested as CXCL12 expression falls and LSK homing failure; however, intratibial injection with CXCL12 effectively facilitated LSK accumulation in bone marrow of Bmi1 KO mice. To try to rescue these defects in Bmi1 KO mice, we generated Bmi1KO/Sirt1Tg (KO-TG) double mutant mice with Sirt1 specific overexpression in mesenchymal progenitor cells (MPCs) in Bmi1 KO mice, and our data showed that KO-TG mice had significantly increased bone-building activity, elevated Cxcl12 expression by MPCs, increased LSK homing and expanded LSK pool in bone marrow compared to Bmi1 KO mice. Of note, similar improvements in KO-TG mice were observed in Bmi1 KO mice fed with dietary resveratrol, an established Sirt1 activator, comparing with KO control mice. Therefore, pharmacologic activation of Bmi1/Sirt1 signaling pathway could simultaneously promote bone-building and hematopoiesis-supportive activities of OBCs.

Plasma Levels of Big Endothelin-1 Are Associated with Renal Insufficiency and In-Hospital Mortality of Immune Thrombotic Thrombocytopenic Purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by severe deficiency of plasma ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. Despite advances in early diagnosis and management, the mortality rate of acute iTTP remains high in a large part of world where access to some of the most novel therapies is limited. To determine the role of plasma big endothelin-1 (bigET-1) or its bioactive product ET-1 as a biomarker and/or a pathogenic factor in acute iTTP, plasma levels of bigET-1 were determined using an immunoassay in patients with iTTP on admission and during remission, as well as in healthy controls; moreover, the biological effect of ET-1 in thrombus formation was determined by a microfluidic assay. We show that plasma levels of bigET-1 were dramatically increased in patients with acute iTTP on admission, which was significantly decreased during clinical response/remission; elevated admission levels of plasma bigET-1 were associated with low estimated glomerular filtration rate, the need for intensive care unit admission or intubation, and in-hospital mortality. Moreover, an addition of a bioactive product ET-1 to cultured endothelial cells in a microfluidic channel significantly accelerated the rate of thrombus formation under arterial flow. Our results demonstrate for the first time a potential role of measuring plasma bigET-1 in patients with acute iTTP in assessing the disease severity and risk of in-hospital mortality, which may help stratify patients for a more aggressive monitoring and therapeutic strategy; also, the bioactive ET-1, derived from bigET-1, may result in acute renal injury in TTP patient, likely through its vasoconstriction and prothrombotic properties.

Eltrombopag restores erythropoiesis in refractory adult acquired pure red cell aplasia.

Acquired pure red cell aplasia is a rare condition characterized by normocytic normochromic anemia with severe reticulocytopenia. In refractory acquired pure red cell aplasia, the low response rate of immunosuppressive therapy also constitutes a challenge. We herein report the case of a 58-year-old male with refractory acquired pure red cell aplasia that was successfully treated by eltrombopag at a dose of 75 mg/day. After application of eltrombopag, the patient achieved complete remission and tolerated the treatment very well, with only mild bilirubin elevation. These preliminary findings showed that eltrombopag may be effective and well tolerated in adult patients with refractory acquired pure red cell aplasia.

Plasma levels of S100A8/A9, histone/DNA complexes, and cell-free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening blood disorder, primarily resulting from autoantibodies against ADAMTS13. Infection or inflammation often precedes acute iTTP. However, the association of inflammation and inflammatory mediators with disease severity and outcome of acute iTTP is not fully assessed. OBJECTIVES: Here, we determined plasma levels of S100A8/A9, histone/DNA complexes, citrullinated histone H3 (CitH3), and cell-free DNA (cfDNA) in a cohort of 108 acute episodes from 94 unique iTTP patients and healthy controls, and assessed the association of each of these biomarkers with the disease severity and mortality. RESULTS: All acute iTTP patients had significantly increased plasma levels of S100A8/A9 (median 84.8, interquartile range [IQR] 31.2-157.4 µg/mL), histone/DNA complexes (median 55.7, IQR 35.8-130.8 U/mL), CitH3 (median 3.8, IQR 2.2-6.4 ng/mL), and cfDNA (median 937.7, IQR 781.3-1420.0 ng/mL) on the admission blood samples when compared with healthy controls. An increased plasma level of S100A8/A9, histone/DNA complex and cfDNA was associated with organ damage, coagulopathy, and mortality in iTTP. After being adjusted for age and history of hypertension, Cox proportional hazard regression analysis demonstrated that a hazard ratio (95% confidence interval) for an elevated plasma level of S100A8/A9, histone/DNA complexes, and cfDNA was 11.5 (1.4-90.9) (P = .021), 10.3 (2.7-38.5) (P = .001), and 12.8 (3.9-42.0) (P = .014), respectively. CONCLUSION: These results indicate that inflammation or plasma inflammatory mediators such as S100A8/A9 or NETosis markers such as histone/DNA complexes and cfDNA may play a role in pathogenesis of iTTP, which may help stratify patients with a high risk of death during acute iTTP episodes.

Elevated plasma levels of syndecan-1 and soluble thrombomodulin predict adverse outcomes in thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13 activity. Despite recent advances in early diagnosis and novel therapeutics, the mortality rate of acute iTTP remains as high as 10% to 20%. Moreover, a reliable clinical and laboratory parameter that predicts disease severity and outcomes is lacking. We show in the present study that plasma levels of syndecan-1 (Sdc-1) and soluble thrombomodulin (sTM) on admission were dramatically increased in patients with acute iTTP and remained substantially elevated in a subset of patients compared with healthy controls. The elevated admission plasma levels of Sdc-1 and sTM were associated with abnormal Glasgow coma scale scores, low estimated glomerular filtration rates, the need for intensive care, and in-hospital mortality rates. Moreover, a further simultaneous increase in plasma Sdc-1 and sTM levels at the time of clinical response/remission (eg, when normalization of platelet counts and substantial reduction of serum lactate dehydrogenase activity were achieved) was highly predictive of iTTP recurrence. These results demonstrate that endothelial injury, resulting from disseminated microvascular thromboses, is severe and persistent in patients with acute iTTP. Plasma levels of Sdc-1 and sTM on admission and in remission are predictive of in-hospital mortality and recurrence of acute iTTP, respectively. Thus, an incorporation of such novel plasma biomarkers into the risk assessment in acute iTTP may help implement a more vigorous and intensive therapeutic strategy for these patients.

P27 deletion enhances hematopoiesis by paracrine action of IL22 secreted from bone marrow mesenchymal stem cells.

Previous studies have reported that p27 deletion stimulates the proliferation of bone marrow mesenchymal stem cells (BM-MSCs) and their differentiation into osteoblasts, it also increases bone marrow hematopoietic progenitor cells (HPCs). However, it is unknown whether the enhanced hematopoiesis induced by p27 deficiency was associated with releasing hematopoietic stem cell (HSC) and HPC supporting factors by BM-MSCs. To answer this question, we cultured the BM-MSCs from wild-type (WT) or p27 knockout (KO) mice, analyzed their proliferation, apoptosis and osteogenesis and harvested their conditioned medium (CM); We also cultured the bone marrow cells (BMCs) with normal medium or CM from WT or KO BM-MSCs and analyzed changes of HSCs and HPCs and colony forming cells (CFCs). Our results showed that the proliferation and osteogenic differentiation of BM-MSCs were increased significantly and their apoptosis was reduced significantly in p27 deficient mice. Simultaneously, we demonstrated that the CM from p27 deficient BM-MSCs stimulated the expansion of HSCs/HPCs more dramatically than that from WT BM-MSCs. Five 2-fold up-regulated proteins were identified in the CM from p27 deficient BM-MSCs by protein chip assays, including interleukin-22 (IL-22), transforming growth factor-ß type I receptor, tumor necrosis factor-related Apoptosis-inducing ligands, VE-cadherin and vascular endothelial growth factor B. We confirmed that expression of IL22 at both mRNA and protein levels were up-regulated significantly in p27 deficient BM-MSCs. The treatment of IL22 increased the percentages of HSCs and HPCs in BMC cultures and the number of CFCs in the colony formation assay, whereas the increased HSC/HPC expansion induced by the CM derived from p27 deficient BM-MSCs was blocked by the addition of anti-IL22 antibody in a dose dependent manner. We also found that the percentages of IL22R1, Stat3 and p-Stat3-S727 positive HSCs and HPCs were increased significantly in p27 deficient BMCs. Our findings in this study indicate that p27 deficiency stimulates HSC/HPC expansion by increasing secretion of IL22 by BM-MSCs and activating IL22-Stat3 signaling in HSCs and HPCs.

Immunosuppressive therapy for elderly-acquired pure red cell aplasia: cyclosporine A may be more effective.

This current study retrospectively analyzed the clinical characteristics of 69 adult patients with acquired pure red cell aplasia (PRCA) including 40 elderly and 29 non-elderly patients from September 2009 to June 2019. The remission induction therapy regimens included cyclosporine A (CsA), corticosteroids (CS), or other immunosuppressive agents. The overall response rate was 55% (22/40) in the elderly group compared with 75.9% (22/29) in non-elderly patients (P = 0.075). In elderly patients, the best remission was achieved in the group treated with CsA than those treated with CS or other immunosuppressive agents (83.3% vs 26.7% vs 42.9%%, P = 0.004). However, outcomes of remission were similar among different treatment groups (P = 0.458) in non-elderly patients. CS induced a higher response rate in the non-elderly than that in the elderly (88.9% vs 26.7%, P = 0.009). By univariate and multivariate analysis, the clinical efficacy of elderly patients with acquired PRCA was closely associated with an induction regimen of CsA (P = 0.009; P = 0.017). In conclusion, CsA might produce higher response rate than CS and other drugs in elderly patients with acquired PRCA.

Induced complete remission faster in adult patients with acquired pure red cell aplasia by combining cyclosporine A with corticosteroids.

To evaluate whether the adult patients with acquired pure red cell aplasia (PRCA) could benefit more from cyclosporine A (CsA) combined with corticosteroids (CS) than CsA or CS alone.Seventy-three patients were evaluated in 2 institutions (6 patients lost to follow-up).The induction therapy included CsA (n = 21), CS (n = 21), or CsA combined with CS (n = 31), and remission was achieved in 16/21 (76.2%), 10/21 (47.6%), and 21/31 (71.0%) patients, respectively. Higher complete remission (CR) rate was achieved in CsA combined with CS group than in CS group (61.3% vs 19.0%, P = .003). Patients achieved CR faster in CsA combined with CS group than in CS group or CsA group (median time, 1 month vs 2 month vs 3 month, P = .010). By multivariate analysis, CsA combined with CS therapy and primary PRCA were the influence factors for CR rate. Twenty-seven patients relapsed due to discontinuation or tapering therapy, and 19 patients regained response by increasing the dose of original regimens or changing to other immunosuppressive therapy. Complete remission to induction therapy was a correlative factor for death (P = .035).CsA combined with CS produced faster and higher CR rate in treating adult patients with PRCA than did CsA or CS alone.

Albumin-to-Fibrinogen Ratio as an Independent Prognostic Parameter in Untreated Chronic Lymphocytic Leukemia: A Retrospective Study of 191 Cases.

PURPOSE: Chronic lymphocytic leukemia (CLL) is one of the most frequent type of B-cell chronic lymphoproliferative disorders and chronic inflammation takes part in the development of CLL. However, there has been no valid immune biomarker to predict the prognosis of untreated CLL patients. MATERIALS AND METHODS: In this retrospective study, we analyzed the clinical correlations and prognostic value of albumin-to-fibrinogen ratio (AFR) detected at diagnosis in 191 CLL patients. RESULTS: The cut-off value of AFR was 9.7 calculated by X-tile. Patients who were more than 65 years old were often accompanied by low level of AFR (p < 0.001). Survival analysis showed that patients with low level of AFR had shorter overall survival (OS) than patients with high level of AFR (p < 0.001). Multivariate analysis illustrated that AFR had a negative impact on OS (p=0.003) and was independent of parameters involved in CLL international prognostic index and other prognostic markers such as CD38 and ZAP-70. CONCLUSION: These data provide a comprehensive view of AFR and shows that AFR at diagnosis is an adverse prognostic factor in untreated CLL patients.

Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4-8) and advanced stage (III-IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P < 0.001) and OS (P < 0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR = 1.90, 95% CI: 1.15-3.16 for PFS, P = 0.013; HR = 2.65, 95% CI: 1.46-4.79 for OS, P = 0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P = 0.0194 for PFS, P = 0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.

Response to cyclosporine A and corticosteroids in adult patients with acquired pure red cell aplasia: serial experience at a single center.

To assess response to cyclosporine A, and/or corticosteroids, and possible factors influencing the response in adult patients with acquired pure red cell aplasia (PRCA). Clinical data from 42 cases were retrospectively analyzed. These patients received cyclosporine A (CsA), and/or corticosteroids (CS), or other immunosuppressive agents on becoming refractory and relapse. Thirty-nine patients were evaluated. Remission induction therapy included CsA (n = 16), CS (n = 13), CsA in combination with CS (n = 6), or other immunosuppressive agents (n = 4). Initial response rates were 75.0, 46.2, 66.7 and 75.0%, respectively (P = 0.456). Cumulative response rates in patients who received CsA, CS, CsA in combination with CS, or other immunosuppressive agents were 69.6% (16/23), 50.0% (7/14), 71.4% (5/7), 42.9% (6/14), respectively (P = 0.376). Cumulative rates of CR were 26.1% (6/23), 28.6% (4/14), 57.1% (4/7), 14.3% (2/14), respectively (P = 0.284). In 27 refractory and relapsed PRCA patients, 11 of 17 patients (64.7%) achieved remission by CsA and/or CS regimen, while three of ten patients (30.0%) responded to other immunosuppressive agents (P = 0.120). CsA and/or CS were effective in treating PRCA. For patients with relapse or refractory PRCA, there were no satisfactory treatments if CsA and/or CS failed or were not administered.

Clinical features of multiple myeloma patients with isolated extramedullary relapse.

This study sought to analyze the clinical features and prognosis of multiple myeloma with isolated extramedullary relapse and with the absence of systemic progression. The clinical features and outcome were retrospectively analyzed in six multiple myeloma patients. These patients had secretory multiple myeloma at diagnosis. When relapsed, the dissociation between medullary and extramedullary response was detected. The serum or urine monoclonal component was extremely low or absent. The plasma cells in bone marrow were <5%. All patients received new targeted therapies (thalidomide or bortezomib) before extramedullary relapse. It is difficult to achieve second remission for them. Even in those showing response, the duration of response was extremely short. The median of overall survival from diagnosis and from extramedullary relapse was 19 months and 6 months, respectively. The overall survival was significantly shorter compared to the patients without extramedullary involvement (84 months, P=0.001). These patients exhibited a special and rare relapse pattern. Patients with this relapse pattern were resistant to current therapies, including novel targeted agents and associated with poor prognosis.

High-resolution epitope mapping by HX MS reveals the pathogenic mechanism and a possible therapy for autoimmune TTP syndrome.

Acquired thrombotic thrombocytopenic purpura (TTP), a thrombotic disorder that is fatal in almost all cases if not treated promptly, is primarily caused by IgG-type autoantibodies that inhibit the ability of the ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) metalloprotease to cleave von Willebrand factor (VWF). Because the mechanism of autoantibody-mediated inhibition of ADAMTS13 activity is not known, the only effective therapy so far is repeated whole-body plasma exchange. We used hydrogen-deuterium exchange mass spectrometry (HX MS) to determine the ADAMTS13 binding epitope for three representative human monoclonal autoantibodies, isolated from TTP patients by phage display as tethered single-chain fragments of the variable regions (scFvs). All three scFvs bind the same conformationally discontinuous epitopic region on five small solvent-exposed loops in the spacer domain of ADAMTS13. The same epitopic region is also bound by most polyclonal IgG autoantibodies in 23 TTP patients that we tested. The ability of ADAMTS13 to proteolyze VWF is impaired by the binding of autoantibodies at the epitopic loops in the spacer domain, by the deletion of individual epitopic loops, and by some local mutations. Structural considerations and HX MS results rule out any disruptive structure change effect in the distant ADAMTS13 metalloprotease domain. Instead, it appears that the same ADAMTS13 loop segments that bind the autoantibodies are also responsible for correct binding to the VWF substrate. If so, the autoantibodies must prevent VWF proteolysis simply by physically blocking normal ADAMTS13 to VWF interaction. These results point to the mechanism for autoantibody action and an avenue for therapeutic intervention.

Assessment of clonality in T-cell large granular lymphocytic leukemia: flow cytometric T cell receptor Vß repertoire and T cell receptor gene rearrangement.

The usefulness of flow cytometric variable ß-chain repertoire (FC-Vß) and T-cell receptor gene rearrangement (TCR-GR) analyses for differentiating T-cell large granular lymphocytic leukemia (T-LGLL) from reactive T-large granular lymphocyte (T-LGL) lymphocytosis has been insufficiently studied to date. In this study, we analyzed the diagnostic value of TCR-GR and FC-Vß analysis in T-LGLL, and compared these results. In our study, FC-Vß analysis was positive in all cases of T-LGLL, and clonality assessment of FC-Vß had equal sensitivity and specificity to GeneScanning analysis but was more sensitive than heteroduplex analysis. Suspected T-cell clonality can best be addressed by evaluating two TCR targets (TCRß and TCRγ), either in parallel or consecutively. Signal transducer and activator of transcription 3 (STAT3) mutation may provide a diagnostic tool for classifying some cases of T-LGL lymphocytosis as true T-LGLL. Our results further demonstrate a significant correlation of STAT3 mutation with pure red cell aplasia, neutropenia, hepatomegaly, ß2-microglobulin and anemia.

Haploidentical hematopoietic stem cell transplantation following myeloablative conditioning regimens in hematologic diseases with G-CSF-mobilized peripheral blood stem cells grafts without T cell depletion: a single center report of 38 cases.

Many Chinese patients with hematologic diseases, who need allogeneic hematopoietic stem cell transplantation (HSCT), lack a human leukocyte antigen-matched donor. To save these patients and to avoid collecting donor bone marrow graft, we adopted haploidentical peripheral blood HSCT with granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cells as the grafts without ex vivo T cell depletion. Thirty-eight patients were enrolled, and they received myeloablative preconditioning. Thirty-five patients attained a successful neutrophil and platelet recovery. The median time for the neutrophil recovery was 16 days (range of 10-23 days), and the median time for the platelet recovery was 19 days (range of 10-66 days). During the follow-up at a median time of 33.1 weeks (range of 1.1-412.6 weeks), eleven (28.9 %) patients developed aGVHD grade I-II and seven (18.4 %) patients developed aGVHD grade III-IV. The incidence of cGVHD was 27.6 %, and nine (23.7 %) patients died within the first 100 days after transplantation. The cumulative survival proportions at 1 and 2 years were 52.51 ± 8.57 % and 43.76 ± 9.11 %, respectively. These results suggested that the G-CSF-primed peripheral blood stem cell grafts, without in vitro T cell depletion, could be an appropriate stem cell source for Haplo-HSCT.

Parathyroid hormone administration improves bone marrow microenvironment and partially rescues haematopoietic defects in Bmi1-null mice.

The epigenetic regulator Bmi1 is key in haematopoietic stem cells, and its inactivation leads to defects in haematopoiesis. Parathyroid hormone (PTH), an important modulator of bone homeostasis, also regulates haematopoiesis, so we asked whether PTH administration improves bone marrow microenvironment and rescues the haematopoietic defects in Bmi1-null mice. The mice were treated with PTH1-34 (containing the first 34 residues of mature PTH), an anabolic drug currently used for treating osteoporosis, and compared with the vehicle-treated Bmi1-/- and wild-type littermates in terms of skeletal and haematopoietic phenotypes. We found that the administration significantly increased all parameters related to osteoblastic bone formation and significantly reduced the adipocyte number and PPARγ expression. The bone marrow cellularity, numbers of haematopoietic progenitors and stem cells in the femur, and numbers of lymphocytes and other white blood cells in the peripheral blood all increased significantly when compared to vehicle-treated Bmi1-/- mice. Moreover, the number of Jagged1-positive cells and percentage of Notch intracellular domain-positive bone marrow cells and protein expression levels of Jagged1 and NICD in bone tissue were also increased in Bmi1-/- mice upon PTH1-34 administration,whereas the up-regulation of PTH on both Notch1 and Jagged1 gene expression was blocked by the Notch inhibitor DAPT administration. These results thus indicate that PTH administration activates the notch pathway and partially rescues haematopoietic defects in Bmi1-null mice, further suggesting that haematopoietic defects in the animals are not only a result of reduced self-renewal of haematopoietic stem cells but also due to impaired bone marrow microenvironment.

Angiogenic factors in chronic lymphocytic leukemia.

Angiogenesis is a complex process controlled by the balance of a large number of regulating factors, the pro- and anti-angiogenic factors. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks for cancer. Recent emphasis on the microenvironment's influence in chronic lymphocytic leukemia (CLL) progression and drug resistance nurtures the interest in angiogenesis. Researchers have already identified a variety of angiogenic factors involved in the CLL, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), angiopoietin-2(Ang-2), thrombospondin-1 (TSP-1), as well as extracellular proteinases such as matrix metalloproteinase-9 (MMP-9). Besides modulating neovascularization, angiogenic factors also participate in the regulation of pro-survival effects of CLL cells. However, the precise mechanism involved still needs to be elucidated further. At present, the levels of some angiogenic factors are regarded as prognostic markers of the progression of CLL, although it is not widely used. Several anti-VEGF agents are currently under clinical trial. Advances in the understanding of the bases of angiogenesis regulators will be benefit for the comprehension of CLL pathogenesis and help to conquer the disease.