scholarly journals Neutropenia in children: acquired neutropenia

2021 ◽  
pp. 66-76
Author(s):  
A.P. Volokha ◽  
Keyword(s):  
Bone Marrow ◽  
Systemic Disease ◽  
Laboratory Finding ◽  
Congenital Infection ◽  
Bone Marrow Aspiration ◽  
Autoimmune Neutropenia ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Severe Infections ◽  
Benign Course

Neutropenia is defined as a reduction in the absolute neutrophil count (ANC) below 1,500 cells/mcl in the blood. Neutropenia is a common laboratory finding in children. It is important to distinguish transient and benign causes from severe congenital neutropenia. Neutropenia can be classified in asymptomatic (mild), moderate, and severe form, the susceptibility to infection depending on ANC. Neutropenia can be either acquired or congenital. Infection, drugs, and immune disorders are the most common acquired causes while congenital causes are rare and confined mostly to infants and children. Transient neutropenia often accompanies viral infections in children, manifested in the period of acute viremia. Young children are characterized by autoimmune neutropenia (AIN), which has a benign course and a favorable prognosis. Autoimmune neutropenia is characterized by a decrease in the number of neutrophils as a result of the destruction of neutrophils in the peripheral blood by antineutrophil antibodies. The duration of AIN is usually 3–5 years. This is a self-limiting disease that in most cases does not require treatment. Despite the benign course, serious infectious complications can occur. Treatment of myeloid growth factors should be started after a previous bone marrow aspiration biopsy in children with severe infections or requiring surgical intervention. High doses of intravenous immunoglobulin and corticosteroids may be effective in treating AIN in patients with life-threating infections. The danger to the patient depends on the etiology, ANC and bone marrow status. The risk of infections is significantly increased in patients with ACN less than 500 cells/μ1. The most common loci of infections include the oral mucosa, skin, perirectal area, perineum. Oral ulcers and gingivitis are characteristic signs of clinically significant neutropenia, requiring the exclusion of its congenital causes. Severe infections in patients with neutropenia are caused by pyogenic or intestinal bacteria and Candida species. It is important to distinguish between transient or benign causes and severe congenital neutropenia or neutropenia associated with serious haematological or systemic disease. Clarification of the cause of neutropenia is important for determining management and prognosis. No conflict of interest was declared by the author. Key words: neutropenia, children, immunodeficiency, autoimmune neutropenia.

scholarly journals 102 Patients with Primary Autoimmune Neutropenia : An Analysis of the European Severe Chronic Neutropenia International Registry (SCNIR)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1039-1039
Author(s):  
Fabian Frömling ◽  
Sabine Mellor-Heineke ◽  
Natali Gerschmann ◽  
Lena Röbbel ◽  
Julia Skokowa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Early Childhood ◽  
Genetic Analysis ◽  
Antibiotic Prophylaxis ◽  
Autoimmune Neutropenia ◽  
Antibody Testing ◽  
Congenital Neutropenia ◽  
Severe Infections

Background: Primary Autoimmune Neutropenia (AIN) is the most frequent type of neutropenia in children with a prevalence of 1/100,000 between infancy and 10 years of age. Primary AIN is caused by anti-neutrophil antibodies binding to neutrophil-specific antigens, resulting in a decrease of circulating neutrophils in the blood, but normal numbers of mature neutrophils in the bone marrow. Typically, primary AIN is present from infancy on until spontaneous remission in early childhood, when anti-neutrophil antibodies disappear. Patients with primary AIN show severe to moderate neutropenia but only rarely suffer from serious infections. Patients remain in the registry for follow up after normalization of blood counts to evaluate late secondary events. Aims: Here we describe the cohort of AIN pts with positive anti-neutrophil antibody testing documented by the European Branch of the SCNIR. We analyzed the course of neutropenia, the frequency of G-CSF treatment for AIN, the incidence of severe bacterial infections and administration of AB prophylaxis. Methods: We identified 102 primary AIN patients within the neutropenia cohort documented by the European Branch of the SCNIR since 1994. We classified primary AIN by positive anti-neutrophil antibody testing (95 pts) or severe neutropenia in peripheral blood with normal bone marrow morphology in patients with age under 5 years (7 pts). Results: Primary AIN has been identified in 102 (61 female; 41 male) pts. The median age of the cohort is 5.18 years (range 1.37-22.71 years), with 630.28 pt years under observation. Median age at diagnosis was 12.07 months (range 0.9-70 months). All pts are currently alive, 40 patients already resolved from primary AIN at a median age of 3.02 years (range 0.83-9.08 years). Median follow-up time after neutropenia had resolved was 2.25 years (range 0-9.27 years). Sixteen of 102 pts (15.7%) received intermittent G-CSF treatment with a median dose of 4.5 µg/kg/day compared to 4.77 µg/kg/day for the congenital neutropenia cohort of the SCNIR Europe. Analysis of infections (tab.1) showed less minor and severe infections comparing to congenital neutropenia (CN) pts. Life-threatening infections like liver abscesses were not seen in primary AIN patients but in 1.8% of CN pts. Twelve AIN pts (11.7%) have received antibiotic prophylaxis for prevention of infection, 6 pts intermittent and 6 pts continuously. However, antibiotic prophylaxis was usually stopped before termination of AIN. Due to the milder course of infections most AIN pts were able to go to Kindergarten and to live a normal life. In 3 pts additional auto-immune related diseases were identified (autoimmune thrombocytopenia, allergic colitis and Kawasaki syndrome) during AIN. Sixteen of 102 AIN patients received genetic analysis, with no mutation being detected. In addition to the 102 AIN pts we identified another 31 CN pts who have initially been classified as AIN due to positive anti-neutrophil antibodies, but who were later genetically confirmed as CN (15 ELANE+, 8 HAX1+, 2 SBDS+, 2 CXCR4+, 2 CSF3R+, 1 G6PC3+). This proportion of pts showed more and more severe infections compared to primary AIN. Genetic testing has been performed in these pts due to ongoing infections and prolonged neutropenia until school age. Conclusions: Pts suffering from primary AIN present with severe to moderate neutropenia. A minority of pts might require G-CSF treatment on demand/interventionally due to antibiotic resistant infections, but long-term G-CSF treatment is regularly not indicated. Primary AIN is a self-limiting condition and in most pts neutropenia resolves until early childhood. Accumulation of secondary diagnoses like autoimmune related diseases, though postulated, has not been confirmed for AIN pts by our data. In AIN pts with severe infections, or prolonged neutropenia CN should be ruled out by genetic analysis and/or bone marrow morphology. Registries are needed to document long-term data on primary AIN pts to analyse potential additional features of primary AIN, possibly other accompanying autoimmune diseases. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficient Correction of HAX1 Mutations in Primary HSPCs of Severe Congenital Neutropenia Patients Using CRISPR/CAS9 GENE-Editing

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-22
Author(s):  
Malte U Ritter ◽  
Benjamin Secker ◽  
Masoud Nasri ◽  
Maksim Klimiankou ◽  
Benjamin Dannenmann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Stem Cell ◽  
Protein Expression ◽  
Healthy Donor ◽  
Live Cell Imaging ◽  
Gene Editing ◽  
Cell Imaging ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia

Patients with the rare pre-leukemia bone marrow failure syndrome severe congenital neutropenia (CN) have markedly reduced numbers of neutrophils in peripheral blood (<500/μl), leading to frequent infections and requiring chronic granulocyte stimulating factor (G-CSF) treatment. Approximately 7 % of CN patients carry homozygous loss-of-function mutations in the HAX1 gene. 25 % of HAX1-CN patients develop MDS or AML. The only curative therapy for CN patients with overt MDS/AML is hematopoietic stem cell transplantation with its associated risks. A clinical need for gene therapy for CN patients is imminent. Here, we describe for the first time the application of CRISPR/Cas9 gene-editing in combination with recombinant adeno associated virus 6 (rAAV6)-based delivery of the template for homology-directed repair (HDR) for the mutated HAX1 gene in primary bone marrow mononuclear CD34+ cells (HSPCs) of HAX1-CN patients. We selected HAX1 mutation p.W44X as the most frequently described mutation in HAX1-CN. We established the delivery of the chemically modified sgRNA in combination with SpCas9 V3 in primary HSPCs using electroporation. The HDR template was generated by PCR from healthy donor HSPCs and cloned into pRC6 vector for the production of high titer rAAV6 (>12x1012 viral copies per ml). Our gene-editing protocol produced on average 79,7 % (± 8,62 %) of total editing (TE) in healthy donor HSPCs (n=6). When we transduced healthy donor HSPCs with rAAV6 containing the template at MOI 105 after electroporation with CRISPR/Cas9 RNP, we achieved 38,1 % (± 1,3 %) knock-in (KI) efficiency and 82,3 % (± 8,2 %) TE (n=2). We further applied this approach to primary HSPCs from 5 CN patients harboring the p.W44X HAX1 mutation. We achieved 84,4 % (± 4,2 %) TE and 65,8 % (± 7,12 %) KI. Too proof, that our editing reintroduced HAX1 protein expression, we performed Western Blot analysis of edited cells (n=2) and were able to detect relevant amounts of HAX1 protein. To assess the effect of HAX1 correction on the neutropenic phenotype in vitro, we performed a liquid culture differentiation assay of edited HSPCs to neutrophils. HSPCs from the same patients that were edited in the AAVS1 safe harbor were used as isogenic controls. In the AAVS1 locus the editing efficiency was 76,74 % (± 17,07 %) total indels. By morphological assessment of Wright-Giemsa stained cytospins of edited cells derived on day 14 of differentiation revealed significant (p = 0,005) increases of mature neutrophils for all five edited HAX1-CN patient samples, as compared to the respective controls. This phenotype correction was also observed in flow cytometry by a significant (p = 0,011) increase of mature CD34-CD45+ CD15+CD16+ neutrophils (n=5). To investigate if the HAX1 mutation correction and reinforced expression of HAX1 protein improved the sensitivity of HSPCs to oxidative stress as described by Klein et al. 2007, we performed live-cell imaging of caspase3/7 activation. Live-cell imaging revealed a substantial reduction of H2O2-induced apoptosis in corrected HAX1-CN patients derived HSPCs (n=3). Furthermore, the corrected differentiated cells were investigated for functional hallmarks of granulocytes. We could observe that HAX1 gene-edited HSPCs showed comparable chemotaxis, phagocytosis and no defects in ROS production to isogenic control edited cells. Taken together, we established a protocol for efficient selection-free correction of HAX1 p.W44X mutation in primary HSPCs using CRISPR/Cas9 and rAVV6 HDR repair templates. Our gene-editing reintroduced HAX1 protein expression in primary HSPCs from HAX1-CN patients. Neutrophils derived from corrected cells showed functional improvements in survival to oxidative stress and general neutrophil functions. We believe that these results are enticing to be investigated further for potential clinical translation as an autologous stem cell therapy for HAX1-CN patients. Disclosures No relevant conflicts of interest to declare.

The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy

Blood ◽  
2013 ◽  
Vol 121 (25) ◽  
pp. 5078-5087 ◽  
Author(s):  
Polina Stepensky ◽  
Ann Saada ◽  
Marianne Cowan ◽  
Adi Tabib ◽  
Ute Fischer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Bone Marrow Transplantation ◽  
Bone Marrow Failure ◽  
Primary Myelofibrosis ◽  
Congenital Neutropenia ◽  
Key Points ◽  
New Gene ◽  
Severe Infections ◽  
Intracellular Storage

Key Points VPS45 is a new gene associated with severe infections and bone marrow failure in infancy that can be treated by bone marrow transplantation. The mutation affects intracellular storage and transport and results in increased programmed cell death in neutrophils and bone marrow.

A Model of Severe Congenital Neutropenia Reveals Signaling Pathways Mediating Mutant Elastase-Triggered Agranulocytosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3070-3070
Author(s):  
Andrew A. Aprikyan ◽  
Tomas Vaisar ◽  
Vahagn Makaryan ◽  
Jay Heinecke
Keyword(s):  
Bone Marrow ◽  
Signaling Pathways ◽  
Myelogenous Leukemia ◽  
Severe Neutropenia ◽  
Myeloid Differentiation ◽  
Cellular Model ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Histone H2b ◽  
Maturation Arrest

Abstract Severe congenital neutropenia (SCN; Kostmann’s syndrome or infantile genetic agranulocytosis) defines an inheritable hematopoietic disorder of impaired neutrophil production due to a “maturation arrest” at the promyelocytic stage of differentiation in the bone marrow. SCN patients have recurring severe infections and often develop acute myelogenous leukemia. We and others reported accelerated apoptosis and cell cycle arrest of bone marrow-derived myeloid progenitor cells in SCN patients with autosomal dominant and autosomal recessive inheritance. Heterozygous mutations in the neutrophil elastase (NE) gene encoding a serine protease, are present in a majority of SCN patients, but not in healthy members of the family, thus indicating a key role of mutant NE in pathogenesis of this disorder. To date, there are no animal or cellular models of SCN as both the knock-in of mutant NE as well as the knock-out of normal NE failed to result in neutropenia phenotype in mice. The molecular mechanisms of mutant NE-mediated severe neutropenia remain largely unknown. We hypothesized that mutations in NE expose the protease to a new range of substrates. To explore this proposal, we established a cellular model of SCN based on tetracycline-regulated expression of mutant NE in human promyelocytic tet-off HL-60 cells that very closely recapitulated the human phenotype. Mutant NE expression resulted in a characteristic block of myeloid differentiation - the cellular hallmark of SCN. Expression of the mutant product was associated with a significant reduction in phosphatidylinosytol-3-kinase and phosphorylated PKB/Akt levels and an imbalance of anti-apoptotic Bcl-2 and pro-apoptotic Bax. These alterations contributed to observed dissipation of mitochondrial membrane potential as determined by FACS analysis, aberrant release of cytochrome C, and accelerated apoptosis. Marked changes in actin cytoskeleton that made the cells more rigid appeared to stem from a reduced level of alpha-actinin and elevated level of Rho GTPase. Immunoprecipitation of cell lysates with elastase-specific monoclonal antibodies followed by mass spectrometric analysis revealed that NE interacted with histone H2B, one of the key components of the nucleosome core of the chromatin. Interestingly, the expression level of histone H2B was substantially reduced in cells expressing mutant NE, therefore supporting the notion of altered substrate specificity of mutant NE. Thus, these observations provide the first evidence that mutant NE affects specific signaling pathways that lead to alterations in cytoskeleton and chromatin reorganization, subsequent apoptosis, and a block of myeloid differentiation in SCN. This cellular model of SCN should provide an invaluable tool for screening potential therapeutic agents capable of preventing maturation arrest and leukemogenesis in subjects suffering from severe congenital neutropenia.

Abnormal Localization of Neutrophil Elastase in Patients with Severe Congenital Neutropenia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1279-1279
Author(s):  
Takashi Sato ◽  
Masakazu Habara ◽  
Hiroki Kihara ◽  
Hiroshi Kawaguchi ◽  
Mizuka Miki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dimensional Analysis ◽  
Protein Trafficking ◽  
Neutrophil Elastase ◽  
Plasma Membranes ◽  
Normal Subjects ◽  
Precursor Cells ◽  
Proteinase 3 ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia

Abstract Mutations in the ELA2 gene encoding neutrophil elastase (NE) in patients with severe congenital neutropenia (SCN) are involved in the pathogenesis of this disorder, possibly due to the abnormal protein trafficking and accelerated apoptosis of myeloid cells. In this study we precisely examined the localization of NE in neutrophils and myeloid precursor cells in bone marrow in patients with SCN using immunofluorescence microscopy equipped with three-dimensional analysis program. Three patients with SCN were enrolled in this study. All patients with SCN showed heterozygous mutation in the ELA2 gene. In normal subjects the pattern of localization of NE in mature neutrophils was almost similar to those of myeloperoxidase (MPO), proteinase 3, lysosomal associated membrane protein 2 (LAMP2). Administration of G-CSF to normal subjects did not affect the pattern of the localization of these proteins in neutrophils. In contrast, mature neutrophils elicited by the administration of G-CSF in patients with SCN NE predominantly localized to the plasma membranes. A small part of NE was detected in the cytoplasmic compartment. The pattern of localization of NE was significantly different from those of MPO, proteinase 3, and LAMP2 in SCN patients, suggesting the abnormal traffic of NE to granules. Adaptor proteins 3 (AP3) specifically shuttles transmembrane cargo proteins from the trans-Golgi to lysosomes. AP3 of myeloid progenitor cells enriched for CD33-positive cells in normal bone marrow was localized in both cytoplasm and plasma membranes. The localization pattern of AP3 was completely consistent with those of NE, MPO, and LAMP2. The localization of AP3 of promyelocytes in patients with SCN was observed in both plasma membranes and cytoplasm. This finding was completely similar to that in normal myeloid precursor cells. However, the localization of NE of promyelocytes in SCN patients was predominantly in plasma membrane. The figures merged apparently presented the different localization of NE and AP3. This result was confirmed by the 3-dimensional analysis with histogram. The localizations of other constituents of primary granules, MPO, poteinase 3, and LAMP2, were consistent with those of AP3. These observations suggest that the mislocalization of NE in myeloid precursor cells in SCN patients does not result from a generalized impairment of protein trafficking but is specific to the mutant NE. The abnormal localization of NE may be involved in the pathogenesis of SCN associated with ELA2 mutation.

Stable Long-Term Risk of Leukemia in Patients with Severe Congenital Neutropenia Maintained On G-CSF Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3206-3206 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Cornelia Zeidler ◽  
Audrey Anna Bolyard ◽  
Blanche P. Alter ◽  
Mary Ann Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cumulative Incidence ◽  
Bone Marrow Failure ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hazard Curve ◽  
Number Of Patients ◽  
Increasing Trend

Abstract Abstract 3206 Poster Board III-143 BACKGROUND G-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODS We updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTS The update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONS For SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. Disclosures Boxer: Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

A Microrna Feed-Forward Loop Amplifies GFI1N382S Transcriptional Reprogramming In Severe Congenital Neutropenia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2239-2239
Author(s):  
Chinavenmeni Subramani Velu ◽  
Avedis Kazanjian ◽  
Clemencia Colmenares ◽  
H. Leighton Grimes
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Transcriptional Repressor ◽  
Dominant Negative ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Feed Forward ◽  
Marrow Cells ◽  
Myeloid Progenitors

Abstract Abstract 2239 The Growth factor independent -1 (Gfi1) transcriptional repressor regulates both hematopoietic stem cell self renewal and myeloid differentiation. Humans with severe congenital neutropenia (SCN) display mutations in GFI1 that generate dominant negative acting proteins. Moreover, GFI1-mutant SCN patients and Gfi1-/- mice display a unique accumulation of myeloid progenitors. Recently we showed that Gfi1 regulation of HoxA9, Pbx1 and Meis1 underlies these phenomena, in that the Gfi1-Hox transcriptional circuit controls the accumulation of myeloid progenitors in vivo. We have also shown that Gfi1 regulates miR-21 during myelopoiesis, and that miR-21 is deregulated by Gfi1N382S expression. Our new data link these concepts by demonstrating that forced expression of miR-21 in bone marrow cells results in the accumulation of myeloid progenitors in transplant recipients. Moreover, miR-21 directly targets the Ski oncoprotein, and Ski-/- bone marrow cells show an accumulation of myeloid progenitors. Thus, Gfi1-/-, miR-21 overexpressing-, and Ski-/- myeloid progenitors accumulate in the marrow. Strikingly, Ski is dramatically reduced in miR-21 overexpressing Lin- bone marrow cells. Nearly undetectable Ski expression in Gfi1-/- bone marrow cells can be completely rescued by antagonizing miR-21 activity. Since Ski is a corepressor and Gfi1 is a transcriptional repressor, we next tested whether the two proteins physically interact. Indeed, endogenous Ski and Gfi1 can be coimmunoprecipitated. Synthetic Ski and Gfi1 proteins reveal that the interaction is mediated through Ski carboxy-terminal and Gfi1 zinc-finger domains. Chromatin immunoprecipitation reveals Ski and Gfi1 co-occupy several Gfi1 target genes (including HoxA9), which are derepressed upon Gfi1 or Ski knockdown. However, while Gfi1 binds and regulates the miR-21 gene, Ski is not bound to the miR-21 gene, and Ski knockdown has no effect upon miR-21 levels. Thus, the data point to a novel feed-forward transcriptional circuit. Gfi1N382S deregulation of miR-21 amplifies the dominant-negative effect of Gfi1N382S through miR-21 targeting of Ski, leading to further derepression of Gfi1-Ski target genes. Disclosures: No relevant conflicts of interest to declare.

Successful Hematopoietic Stem Cell Transplantation Using an Immunosuppressive Conditioning Regimen in Ten Patients with Severe Congenital Neutropenia: A Single-Institute Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3688-3688
Author(s):  
Yoko Mizoguchi ◽  
Mizuka Miki ◽  
Aya Furue ◽  
Shiho Nishimura ◽  
Maiko Shimomura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hematopoietic Stem ◽  
Engraftment Failure

Abstract Severe congenital neutropenia (SCN) is a rare heterogeneous genetic disorder characterized by severe chronic neutropenia, with absolute neutrophil counts below 0.5×109/L, and by recurrent bacterial infections from early infancy. Granulocyte colony-stimulating factor (G-CSF) is widely used for the treatment of neutropenia in patients with SCN. However, the long-term G-CSF therapy has a relative risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The only curative treatment available for SCN patients is hematopoietic stem cell transplantation (HSCT). Recently, HSCTs with reduced intensity conditioning (RIC) regimens have been applied to the treatment of SCN patients without malignant transformation who have become G-CSF refractory. However, the optimal conditions of HSCT for SCN patients have not been established. In this study, we conducted bone marrow cell transplantations (BMT) in ten patients with SCN using an immunosuppressive conditioning regimen to minimize early and late transplant-related morbidity in Hiroshima University Hospital. Ten patients with a total of 11 HSCT procedures in our institution (performed from 2007 to 2015) were enrolled in this study. Four of the ten patients had experienced engraftment failure of the initial HSCT and three of them were referred to our hospital for re-transplantation. Heterozygous mutation inthe ELANE gene was identified in nine of ten patients. These nine patients received BMT less than 10 years of age. All ten patients had recurrently experienced moderate to severe bacterial or fungal infection before HSCT and received temporal or regular administration of G-CSF. Bone marrow cells (BM) were obtained from five HLA-matched related (MRD), three HLA-matched unrelated (MUD), and three HLA-mismatched unrelated (7/8) donors (MMUD), respectively. The conditioning regimen basically consisted of fludarabine (100 to 125 mg/m2), cyclophosphamide (100 to 150 mg/kg), melphalan (70 to 90 mg/m2), total body irradiation (3 to 3.6 Gy), and/or anti-thymocyte globulin (10 to 12 mg/kg). Short-term methotrexate and tacrolimus were administered for the prophylaxis of graft-versus-host disease (GVHD). Engraftment of neutrophils was successfully observed within 24 days of post-transplantation in all patients. All patients achieved complete chimerism at the time of engraftment. Two patients who underwent BMT from MRD and one patient who underwent BMT from MUD showed the gradual decrease of donor-derived cells. Donor lymphocyte infusion treatment successfully achieved the complete chimerism or stable mixed chimerism in these 3 patients. Although 3 patients experienced the acute GVHD (Grade I-II), the addition of glucocorticoids to tacrolimus prevented the extension of acute GVHD. Only one patient developed mild chronic GVHD presenting limited type of skin involvement. All patients are alive for 9 months to 9 years after HSCT with no signs of severe infections or transplantation-related morbidity. Our results demonstrate that BMT together with a sufficient immunosuppressive conditioning regimen may be a feasible and effective treatment for SCN patients, irrespective of initial engraftment failure. Although our results through the small number of cohort is limited to conclude, the BMT with the optimal donors may lead to the increased opportunity for lower risk of SCN patients especially at younger age as a curative treatment. The further analyses of accumulated cases are necessary to assess the efficacy, safety, and less late adverse effects related to HSCT including fertility. Disclosures No relevant conflicts of interest to declare.

Spontaneous remission of granulocyte colony-stimulating factor–associated leukemia in a child with severe congenital neutropenia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3647-3649 ◽  
Author(s):  
Sima Jeha ◽  
Ka Wah Chan ◽  
Andrew G. Aprikyan ◽  
W. Keith Hoots ◽  
Steven Culbert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Allogeneic Bone Marrow Transplantation ◽  
Spontaneous Remission ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Stimulating Factor

Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.

scholarly journals Acral Persistent Papular Mucinosis associated with Multiple Myeloma - Unknown Presentation

JMS SKIMS ◽  
2012 ◽  
Vol 15 (1) ◽  
pp. 74-75
Author(s):  
Mushtaq Ahmad ◽  
Farhana Siraj ◽  
Mubashir Ahmad ◽  
Shabir Ahmad
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Histopathological Examination ◽  
Systemic Disease ◽  
Disease Patient ◽  
Bone Marrow Aspiration ◽  
X Ray ◽  
Heterogenous Group ◽  
Lytic Lesions

The cutaneous mucinosis are a heterogenous group of disorders in which mucin accumulates in the skin. A 66 years old man presented with asymptomatic flesh coloured papules on the extremities without any truncal involvement of 3 months duration. Histopathological examination of a lesional biopsy revealed unremarkable epidermis with dermis showing pallor and loosening of collagen bundles in mucin like deposition suggestive of cutaneous mucinosis. Patient was put on steroids and hydroxycholoroquinine. Three months later he presented with encephalopathy. Investigation revealed hypercalcaemia, reversal of albumin globulin ratio, azotemia. X-ray skull revealed lytic lesions. Bone marrow aspiration and bone marrow biopsy was suggestive of multiple myeloma. This is an unknown presentation, as localized cutaneous mucinosis is not associated with systemic disease. Patient was started on chemotherapy for multiple myeloma. JMS 2012;15(1):74-75.

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