Can Exposure to Jet Fumes Lead to Acute Leukemia?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5535-5535
Author(s):  
Maged F. Khalil ◽  
Ashish Sangal ◽  
Alka Arora ◽  
Seema Niak ◽  
Zili He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ionizing Radiation ◽  
Peripheral Blood ◽  
De Novo ◽  
Bone Biopsy ◽  
Alkylating Agents ◽  
Previous History ◽  
Chromosome 17 ◽  
Acute Myelocytic Leukemia ◽  
History Of

Abstract Introduction: AML/MDS is usually diagnosed in older adults with median age of 64 in patients at time of diagnosis, after occupational exposure to organic solvents, such as benzene, or previous therapeutic exposure to alkylating agents, topoisomerase inhibitors, or ionizing radiation. We are presenting a case of AML/MDS in a young female without previous history of exposure to alkylating agents or ionizing radiation, but with history of exposure to jet fumes. Case Report: This is a 30-year old Carribean woman, chronic smoker, ethanol user, employed for eight years at the airport, working on the ground with heavy direct exposure to jet fumes, who presented with 2 weeks of progressive dyspnea, fatigue and bone pains. She was found to have pancytopenia, hemoglobin 2.8 gm/dL, platelets 37,000/mL, and neutrophils 1100/mL. Peripheral smear showed many nucleated red blood cells and blasts. Bone marrow aspiration was “dry” and bone biopsy revealed hypercellularity with dysplastic changes in erythrocyte, granulocyte and megakaryocytic lineages with 46% blasts. Flow cytometry of peripheral blood showed positivity for CD13, CD33, CD34, and CD117 and HLA-DR with complex cytogenetics showing deletions involving chromosomes 5q, 7q, 12p, 20q and loss of chromosome 17. Fluorescent in situ hybridization (FISH) studies were negative for t(15,17), MLL, t(8,21), inv(16) seen in classical de novo AML. FISH also did not show abnormalities in the probe regions 5q31, 7q31, 8cen and 20q12 of chromosomes 5, 7, 8 and 20 classically seen in de novo MDS. The blast cell morphology suggested acute myelocytic leukemia on a background of myelodysplasia. Precise FAB subtype was not possible in the absence of special stains like myeloperoxidase, and specific and non-specific esterase stains. The patient was treated with two induction courses of cytosine arabinoside and idarubicin. With persistence of 4.5% blasts on the peripheral blood and severe bone marrow aplasia, she was referred for allogeneic stem cell transplantation, in view of failed induction remission and complex cytogenetics at presentation. Conclusion: Case-control studies of leukemia demonstrated only slight increase in risk of disease after many years of occupational or chemical exposures. More studies to investigate leukemia incidence in airport employees, or even communities near airports are needed.

GATA2 Mutations In Nonsyndromic Pediatric Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2778-2778
Author(s):  
Amy Hsu ◽  
M. Monica Gramatges ◽  
Christopher Williams ◽  
Brian Yang Merritt ◽  
M. Tarek Elghetany ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Family History ◽  
Myelodysplastic Syndrome ◽  
Splice Site ◽  
Peripheral Blood ◽  
De Novo ◽  
Nk Cell ◽  
Monosomy 7 ◽  
Dysmorphic Features ◽  
History Of

Abstract Myelodysplastic syndrome (MDS) is rare in children. Certain inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia, severe congenital neutropenia and Shwachman Diamond syndrome, markedly increase the risk of MDS during childhood. However, the genetic factor(s) underlying sporadic pediatric MDS are unknown. Germline mutations in GATA2, a hematopoietic transcription factor, explain four MDS-predisposing conditions: monocytopenia and mycobacterial infection (MonoMAC); dendritic cell, monocyte, B and NK cell lymphoid deficiency (DCML); primary lymphedema with myelodysplasia progressing to acute myeloid leukemia (Emberger syndrome); and a subset of familial MDS. Cases of pediatric MDS have been observed in some of the reported pedigrees. In addition, three individuals have been reported with large, de novo deletions encompassing GATA2 and surrounding genes and manifesting developmental delay, intellectual disability and dysmorphic features alongside their hematologic abnormalities. We identified a novel GATA2 splice site variant (c.1018-2A>C) in a teenager with MDS, WHO classification refractory cytopenia of childhood (RCC). Although he was found to have monocytopenia and B and NK cell deficiencies, he had no history of infections associated with MonoMAC or pertinent family history. We, therefore, hypothesized that mutations in GATA2 might be present in additional cases of pediatric MDS that were neither associated with an IBMFS nor relevant personal or family history. Two Baylor College of Medicine biology studies open to children with hematologic disease were queried for patients with the diagnosis of MDS. Exclusion criteria included treatment-related MDS, diagnosis of an IBMFS, prior diagnosis of severe aplastic anemia or infections suspicious for MonoMAC or DCML, and known or suspected family history of a GATA2-associated disorder. Cases lacking a pre-hematopoietic stem cell transplantation (HSCT) tissue sample available for study were also excluded. In addition to the patient described above, six children were identified who met eligibility criteria. DNA was isolated from banked peripheral blood or bone marrow cells and GATA2 sequencing performed, including upstream and intronic regulatory regions. Array comparative genomic hybridization was also performed on one sample that lacked GATA2 sequence variants, but was notable for complete absence of heterozygosity (AOH), including 6 polymorphic sites with minor allele frequencies of 0.20 or greater. Pertinent clinical and laboratory features were extracted by medical record review blinded to GATA2 status. We found heterozygous GATA2 mutations in three of the six additional patient samples. Thus, four of this seven patient, pediatric MDS cohort had mutated GATA2. Two of the newly identified mutations were splice site variants: a previously described c.1018-1G>A and a novel variant altering the exon 7 splice site acceptor (c.1114-1G>C). The third mutation was a de novo 3.1-3.3 Mb deletion encompassing the entire GATA2 locus and contiguous genes, and was established to be germline by analysis of skin fibroblasts. Notably, the patient had normal neurocognitive development and was without dysmorphic features. Their ages of presentation were 5, 9, 12 and 15 years. With the exception of the initial case, peripheral blood T and B cell phenotyping was not obtained prior to HSCT. Monocytopenia of less than 200/µL was present in five of seven patients, three of whom had a GATA2 mutation. All four GATA2 mutation cases had RCC and three of the four had monosomy 7 at diagnosis. In contrast, the three cases lacking GATA2 mutation presented with the MDS classification refractory anemia with excess blasts (RAEB-2), with either a normal karyotype, complex karyotypic changes or chromosome 13.q12q14 deletion. GATA2 mutation may explain a significant portion of sporadic, seemingly nonsyndromic pediatric MDS, particularly cases with monosomy 7. Evaluation of larger cohorts is warranted to ascertain the true prevalence. Although this cohort is small, we recommend GATA2 sequencing be performed as part of the initial evaluation of pediatric MDS as the identification of a germline mutation has critical implications for related donor selection and genetic counseling. AOH in GATA2 sequencing should prompt deletion analysis, even in cases without infections, dysmorphic features or neurocognitive impairment. Disclosures: No relevant conflicts of interest to declare.

Prolonged Survival of a Patient with De Novo Acute Myeloid Leukemia (AML) and Trisomy 13 with Intensive Chemotherapy and Autologous Peripheral Blood Transplantation (PBSCT): A Case Report.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4519-4519
Author(s):  
Nitin D. Joshi ◽  
Alpesh Amin ◽  
Rajneesh Nath
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Bone Marrow Biopsy ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
De Novo ◽  
Trisomy 13 ◽  
Autologous Pbsct ◽  
De Novo Aml ◽  
First Complete Remission

Abstract Trisomies are uncommon cytogenetic abnormalities in patient with de novo AML. Survival of patients with trisomy 13 ranges from 0.5 to 14.7 months. We present the treatment outcome of a 71-year-old man with de novo AML and trisomy 13 who had PBSCT in first complete remission. A 71-year Puerto Rican male was diagnosed with AML in April 2003. His CBC showed WBC count 177 K/mm3, hemoglobin 10.3 gm/dl, platelets 43 K/mm3 and blast cells 75%. Flow cytometry revealed that the leukemic blasts were CD33, CD13, CD11c and CD56 positive but negative for CD34. Cytogenetics failed to yield any metaphases. Peripheral blood FISH studies revealed trisomy 13 positivity in 300 of 325 cells analyzed. Patient received induction chemotherapy with high dose Ara-c (HiDAC) 3g/m2 QD x 5 doses and mitoxantrone 80mg/m2 on day # 2. Bone marrow done day 28 post induction chemotherapy revealed residual leukemic blasts. Cytogenetics showed that one out twenty metaphases had trisomy 13 along with translocation t (9:18) (q34; q10). 11.9% of cells had trisomy 13 by FISH analysis. The patient then received a second cycle of chemotherapy with HiDAC at 2 g/m2 Q12 x 12 doses. Bone marrow biopsy on day 35 following reinduction chemotherapy revealed normocellular-regenerating marrow in remission and FISH was negative for trisomy 13. On the third cycle of chemotherapy, patient received Etoposide 11 mg/kg. Neupogen was started on day #3 and 10.3 x 106 CD34 positive cells/kg were collected. The patient then underwent autologous PBSCT using Melphalan 160 mg/m2 as the preparative regimen. On Day +87 and Day +182 post transplant, bone marrow biopsy showed complete remission with FISH negative for trisomy 13. The patient is still alive 27 months after initial treatment and 22 months post PBSCT. Autologous PBSCT in first complete remission for AML with trisomy 13 may provide a superior survival than chemotherapy alone.

Study of Sequential Treatment of Newly Diagnosed De Novo AML Patients with DA and CAG Regimens as Remission Induction Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4630-4630
Author(s):  
Hui ping Sun ◽  
Wei Hong Liu ◽  
Jun min Li ◽  
Qiu sheng Chen ◽  
Yu Chen
Keyword(s):  
Bone Marrow ◽  
Induction Therapy ◽  
Peripheral Blood ◽  
De Novo ◽  
Classification Criteria ◽  
Sequential Treatment ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
Fab Classification ◽  
De Novo Aml

Abstract Objectives To evaluate the efficacy and safety of sequential treatment of newly diagnosed de novo AML patients with DA and CAG regimens as induction therapy. Methods Those who were newly diagnosed as de novo AML (FAB classification criteria) were enrolled and DA regimen chemotherapy were administered. Bone marrow aspirates were performed and BM smears were examined at 48 hours since the end of chemotherapy. If severe hypocellularities were not achieved, the percentage of blasts in BM was between 20%–60% and peripheral WBC was in the range of (0.5–10) x109/L, the patients would receive CAG regimen therapy since 72 hours. Patients’ general status and the important parameters, such as peripheral blood count, liver function, renal function, thrombosis and hemostasis parameters were monitored throughout the course of the treatment and thereafter. When the clinical symptoms were relieved and peripheral blood counts returned to normal, or it was the end of the second or third week since the end of the CAG regimen, Bone marrow were examined again to evaluate the efficacy of the sequential therapy. Results 14 patients consisted of 9 male and 5 female patients were enrolled. Out of them, 2 were M1, 5 M2, 4 M4 and 3 M5 according to FAB classification criteria. Median of blasts in BM were 38.5%(20%–60%) before CAG regimen. Of the 14 patients, 10 reached CR, 2 PR and 2 NR. CR rate was 71.4% (10/14) and total response rate was 85.7%(12/14). Time to achieve CR was on 15th(14th–29th)day medianly since the end of the treatment. During the CAG therapy courses, the nadir of peripheral blood cell counts and the time when it occurred were as follows: WBC 1.0(0.2–3.5)(x109/L),10(1–23)(d); Hb 57.5(44–69) (g/L), 10(1–27)(d)and PLT 11.5(10–65)(x109/L), 12(3–23)(d), respectively. Neutropenia (WBC<1.0x109/L) and thrombocytopenia (PLT<20.0x109/L) were lasted for 0(0–24) and 11(0–21)days, respectively. Median units of transfusions of platelets and red blood cells required by each patient were 3(0–10)(u) and 4(0–12)(u), respectively. The most commonly observed side effect of the regimen was bone marrow proliferation inhibition. Infections, usually respiratoy tract infections, were the second. However, sepsis was rare, which appeared in 1 out of 14 patients. Conclusions DA and CAG regimens sequential treatment as remission induction chemotherapy in patients with newly diagnose de novo AML was highly effective and well tolerated. It would be beneficial for those who might not be sensitive enough to DA regimen chemotherapy only.

Secondary Acute Myeloid Leukemia (AML), Including Therapy-Related AML, Associates with Worse Treatment Outcomes, Than De Novo AML Even After Hematopoietic Stem Cell Transplantation, and Its Unfavorable Behavior Does Not Associated with Functional Activity of p-Glycoprotein, MDR1

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2157-2157
Author(s):  
Boram Han ◽  
Ha Yeon Lee ◽  
Jun Ho Yi ◽  
Jun Ho Jang ◽  
Kihyun Kim ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Functional Activity ◽  
De Novo ◽  
Risk Group ◽  
Previous History ◽  
Risk Groups ◽  
Hematopoietic Stem ◽  
P Glycoprotein ◽  
History Of ◽  
De Novo Aml

Abstract Abstract 2157 Background: Secondary acute myeloid leukmia (AML; sAML) is a distinct disease entity among AMLs. It usually includes AMLs with previous history of myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN), and therapy-related AMLs (tAMLs) developed after exposure to leukemogenic chemotherapy or radiation therapy. It has been known that its prognosis is very poor with median survival of less than 1 year, and that allogeniec hematopoietic stem cell transplantation (HSCT) is the only curative treatment modality with improving clinical outcomes. The current study evaluated clinical characteristics, treatment outcomes in patients with sAML, the impact of cytogenetic risk group or functional activity of p-glycoprotein, related to multidrug resistance 1 (MDR1), on the treatment outcomes in sAML compared to those in de novo AML (dAML). Methods: A total of 441 consecutive AML patients diagnosed at the Samsung Medical Center, Seoul, Korea between Jan 2002 and Jun 2010 were included in this retrospective study. Out of them, 76 patients (17.2%) were sAML, among whom 39 patients (8.8%) had previous history of MDS or MPN and 37 patients (8.4%) were tAML. The overall survival (OS) and event free survival (EFS) were evaluated according to the cytogenetic risk group and the performance of HSCT, in addition to other clinical risk factors. Furthermore, P-glycoprotein assay for multidrug resistance 1 (MDR1) functional activity was performed. MDR1 functional activity was calculated by verapamil-inhibited rhodamine-123 efflux activity minus uninhibited rhodamine-123 efflux activity, and positivity was determined as equal to or over 5% MDR activity. Results: In sAML, a trend of higher frequency of unfavorable cytogenetic group was noted (23.7% in sAML vs 13.7% in dAML). The OS and EFS were significantly shorter in sAML than in dAML. Median OS duration was 12.8 months in sAML, but not reached in dAML (p<0.001), while that of EFS was 8.5 months in sAML, vs. 28.1 months in dAML (p<0.001). Confined to intermediate cytogenetic risk group, sAML group showed shorter OS than dAML group (8.0 months vs 55.1 months; p<0.001). However, no difference of OS was noted between sAML vs dAML in favorable (not reached vs not reached; p=0.4) or unfavorable cytogenetic risk groups (16.5 months vs 11.2 months; p=0.7), respectively. With respect to EFS, when confined to intermediate cytogenetic risk group, sAML group showed shorter EFS than dAML group (5.7 months vs 19.9 months; p<0.001). No difference of EFS was noted between sAML vs dAML in unfavorable cytogenetic risk groups (12.6 months vs 7.9 months; p=0.9). Of interest, in favorable cytogenetic risk group, adverse impact of sAML over dAML on EFS was suggested (15.4 months vs not reached, p=0.1). The patients receiving HSCT for sAML showed better survival compared to those not receiving HSCT for sAML (p<0.001). Among patients receiving HSCTs, OS of sAML patients was still shorter than that of dAML patients (28.3 months vs not reached, p=0.01). Even more, among patients without receiving HSCT, OS of sAML patients was significantly shorter than that of dAML patients (4.4 month vs 28.3month, p<0.001), thus still requiring further improvement of HSCT outcomes in sAML. In terms of MDR1 activity, no difference of MDR1 positivity was noted between sAML (60.6% [n=20/33]) and dAML (61.9% [n=117/189]; p=0.8). Also, mean MDR1 activity was indifferent between in sAML and dAML groups (12.5±2.9% in sAML, 13.4±1.8% in dAML, p=0.8). This finding suggested that MDR1 may not be resopnsbile for drug resistance in patients with sAML, thus other mechanism needs to be investigated for unfavorable characteristics of sAML. Conclusion: The current study suggested that 1) the patients with sAML showed a poorer outcome especially in intermediate cytogenetic risk group; 2) HSCT could improve treatment outcomes of sAML patients, but transplant outcome in sAML patients is still inferior to that in dAML patients receiving HSCT; 3) MDR1, one of important resistance mechanism of AML, may not be the case for resistance in sAML. Disclosures: No relevant conflicts of interest to declare.

Will a Peripheral Blood (PB) Sample Yield the Same Diagnostic and Prognostic Cytogenetic Data as the Concomitant Bone Marrow (BM) In Myelodysplasia? An International Study Comparing Cytogenetics and Interphase FISH Using Parallel PB and BM Samples

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2922-2922
Author(s):  
Athena M Cherry ◽  
Marilyn L. Slovak ◽  
Lynda J Campbell ◽  
Kathy Chun ◽  
Virginie Eclache ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Research Funding ◽  
De Novo ◽  
International Study ◽  
Chromosome Abnormalities ◽  
International Prognostic Scoring System ◽  
Second Phase ◽  
Interphase Nuclei ◽  
Interphase Fish

Abstract Abstract 2922 The myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by ineffective hematopoiesis and a highly variable clinical course, for which novel treatments are beginning to emerge. Conventional cytogenetic studies (CCS) of bone marrow (BM) are routinely used in clinical practice to detect abnormal clones in proliferating (metaphase) cells, identifying clonal aberrations in ∼50% of de novo MDS cases. Cytogenetics is also one of the key International Prognostic Scoring System (IPSS) components used to estimate overall survival and leukemia-free survival in MDS. Chromosome abnormalities may be quantified at presentation and during treatment by the use of fluorescence in situ hybridization (FISH) with DNA probes for specific chromosome loci (e.g., chromosomes 5, 7, 8 and 20) in non-proliferating (interphase) nuclei. However, it is not clear whether or not peripheral blood CCS will yield the same diagnostic and prognostic data as bone marrow CCS at disease presentation or whether patients without apparent chromosome abnormalities by CCS have “hidden” abnormalities that can be identified by interphase FISH. To answer these questions, 15 members of the International Working Group on MDS Cytogenetics agreed to perform CCS and FISH in parallel on both peripheral blood and bone marrow samples collected from MDS patients. To be certain that all participating sites scored and interpreted their individual FISH data in a similar fashion, a quality assurance (QA) study was completed with each site studying two identical test (proficiency) samples. Concordance among sites was very good to excellent allowing for the establishment of a standardized protocol with clear scoring criteria before patient samples were processed. In the second phase of the study, a total of 77 MDS patients were accrued to the study with 61% showing an abnormal karyotype. A FISH panel consisting of eight probe sets [-5/5q-, -7/7q-/der(1;7), +8/8q-, -11/+11/11q-/add(11q), 12p-/+21/t(12;21), -13/13q-, 17p- and 20q-/i(20q)/i(20p), Abbott Molecular, Inc.] was performed on both specimen types. While CCS was frequently unsuccessful (57.5%) in the PB specimens, FISH was informative (concordant with BM/PB CCS) in 92% of cases, with 49% of PB FISH demonstrating an abnormal clone. FISH was discordant in 4 of 77 BM and PB samples (5%), while CCS and FISH on BM and PB were discordant in 6 of 77 BM specimens (8%) and 6 of 73 PB specimens (8%). The data suggest that evaluation of interphase nuclei from PB on follow-up (non-diagnostic) FISH studies on MDS patients will be equally informative (and less costly and stressful) as a BM sample. Disclosures: Slovak: PerkinElmer: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. Ohyashiki:Nippon Shinyaku Co., Ltd.: Research Funding.

Circulating Megakaryocyte-Derived Cells Detected by Flow Cytometry As Marker of Aggressive Neoplasms of Megakaryocytic Lineage in Acute Megakaryoblastic Leukemia and Allied Malignancies Presenting As Primary Myelofibrosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1461-1461
Author(s):  
Serena Marotta ◽  
Giovanna Giagnuolo ◽  
Giulia Scalia ◽  
Maddalena Raia ◽  
Santina Basile ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Differential Diagnosis ◽  
Cell Population ◽  
Peripheral Blood ◽  
Primary Myelofibrosis ◽  
Giant Platelets ◽  
Megakaryoblastic Leukemia ◽  
History Of ◽  
Blast Cells

Abstract Abstract 1461 The differential diagnosis of myelofibrotic disorders encompasses chronic primary myelofibrosis (PMF), myelodysplastic syndromes with fibrosis (MDS-F), acute panmyelosis with myelofibrosis (APMF) and acute megakaryoblastic leukemia (AMKL). Most of these conditions are recognized as distinct entities by the WHO 2008 revised classification of myeloid neoplasms; however, the WHO admits that often a definitive diagnosis is problematic, mostly because of specimens with insufficient cellularity (e.g., “dry tap”). Nevertheless, the correct identification of the most aggressive fibrotic disorders (APMF and AMKL) remains crucial, given their poor prognosis and subsequent need of intensive treatment (including transplantation). Even the most recent molecular studies did not result in any contribution in the differential diagnosis. Here we report our experience on a cohort of about 300 patients who were admitted in our bone marrow failure unit because of cytopenia in the last 7 years. All these patients were evaluated by standard peripheral blood and bone marrow cytology, karyotype analysis and bone marrow thephine biopsy, aiming to a definitive hematological diagnosis. Flow cytometry analysis was performed at initial presentation and then serially during the follow up on both peripheral blood and bone marrow aspirate. All patients were classified according to the WHO 2008 revised classification of myeloid neoplasms, and received the best standard treatment based on the specific disease, age and comorbidities. This report focuses on 8 patients who shared a unique flow cytometry finding of an aberrant megakaryocyte-derived cell population, which seems associated with a distinct disease evolution. Two of these patients received the diagnosis of AMKL according to bone marrow aspirate and trephine biopsy; the karyotype was complex in one case (monosomal karyotype, including a 5q-), whereas no Jak-2 mutation or any other genetic lesions could be demonstrated. Their blast cells were CD34+, CD38+, CD45+, CD117+, CD33+, CD13+; in addition, in the peripheral blood, we detected the presence of an aberrant cell population which was CD45-, CD42b+ (CD34+ in one case and CD34- in the other one). In the blood smear, we observed megakaryocyte fragments which likely correspond to this aberrant cell population, as identified by flow cytometry. Other three patients presented with a severe pancytopenia: all of them had a dry tap, and their trephine biopsies documented a massive fibrosis. They had no previous hematological disorder (one suffered from Behcet syndrome), normal karyotype and absence of any typical genetic lesion (i.e., wild-type Jak-2). All of them did not show splenomegaly, increased LDH or leukoerythroblastosis; their peripheral blood smear showed abnormal giant platelets, often resembling megakaryocyte fragments. Flow cytometry documented in the peripheral blood the presence of a distinct population of CD45-, CD42b+, CD61+ cells, which was also CD34+ in one case. These 3 patients were initially classified as PMF, even if APMF could not be ruled out; however, within 6 months they all progressed to AMKL. At this stage, typical CD34+, CD45+ blast cells were accompanied by a progressive increase of CD45+, CD42b+, CD61+ cells. This aberrant megakaryocyte-derived cell population (which could not be demonstrated in patients with thrombocytopenia) was also identified in 3 additional patients, who have a previous history of hematologic disorders: two had a history of pure red cell aplasia (successfully treated by immunosuppressive therapy), and one a 5q- melodysplastic syndrome (responding to lenalidomide, even with transient cytogenetic remission). In all of them we observed the appearance of CD45-, CD42b+ cells in the peripheral blood, which appeared as giant platelets/megakaryocyte fragments in the blood film; this finding within a few weeks was followed by progression to AMKL (5q- was detected in 2 of 3 cases). In conclusion, we demonstrate that aberrant circulating megakaryocyte-derived cells detected by flow cytometry may be useful in the differential diagnosis of myelofibrotic disorders. These giant platelets or megakaryocyte fragments, regardless the initial diagnosis, were associated with early evolution into AMKL, likely representing a surrogate marker for aggressive neoplasms of the megakaryocytic lineage. Disclosures: Risitano: Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Dnmt3b Is Dispensable for Hematopoietic Stem Cell Differentiation, but Acts Synergistically with Dnmt3a to Control the Balance Between Self-Renewal and Differentiation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 848-848
Author(s):  
Allison Mayle ◽  
Grant Anthony Challen ◽  
Deqiang Sun ◽  
Mira Jeong ◽  
Min Luo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
De Novo ◽  
Annexin V ◽  
Dna Methyltransferases ◽  
Self Renewal ◽  
Minimal Impact ◽  
Hsc Transplantation

Abstract Abstract 848 DNA methylation is an epigenetic modification in vertebrate genomes critical for regulation of gene expression. DNA methylation is catalyzed by a family of DNA methyltransferase enzymes, Dnmt1, Dnmt3a, and Dnmt3b. Dnmt1 is primarily a maintenance methyltransferase, targeting hemimethylated DNA to reestablish methylation marks after DNA replication. Dnmt3a and Dnmt3b are de novo methyltransferases that are essential for normal embryonic development. In humans, somatic mutations in DNTM3A have been identified in ∼20% of human acute myeloid leukemia (AML) and ∼10% of myelodysplastic syndrome (MDS) patients, but the mechanisms through which these mutations contribute to pathogenesis is not well understood. Congenital mutations in DNMT3B can cause ICF (immunodeficiency, centromeric instability, and facial anomalies) syndrome. These patients exhibit chromosomal instability due to heterochromatin decondensation and demethylation of satellite DNA. Our group has recently reported that Dnmt3a is essential for HSC differentiation (Challen Nature Genetics, 2011). Conditional knockout of Dnmt3a (Dnmt3a-KO) resulted in HSCs that could not sustain peripheral blood generation after serial transplantation, but phenotypically defined HSCs accumulated in the bone marrow. Dnmt3b is also highly expressed in HSCs, but its contribution to gene regulation in hematopoiesis is unclear. Here, we examine the role of Dnmt3b, alone and in combination with Dnmt3a KO, in the regulation of hematopoiesis. We performed conditional ablation of Dnmt3b, as well as Dnmt3a and Dnmt3b simultaneously using the Mx1-cre system. Unlike the Dnmt3a-KO HSCs, loss of Dnmt3b had a minimal impact on blood production. Even after several rounds of transplantation, 3b-KO HSCs performed similarly to WT controls. However, the Dnmt3ab-dKO (double knock-out) peripheral blood contribution was quickly and severely diminished, accompanied by a dramatic accumulation of Dnmt3ab-dKO HSCs in the bone marrow (Figure 1). The dKO phenotype paralleled that of the 3a-KO HSC, but was more extreme. To examine the impact of loss of Dnmt3a and -3b on DNA methylation in HSCs, we performed Whole Genome Bisulfite Sequencing (WGBS) on Dnmt3a-KO, Dnmt3ab- dKO and control HSCs. As we previously found with more limited DNA methylation analysis, loss of Dnmt3a led to both increases and decreases of DNA methylation at distinct genomic regions (Challen, Nature Genetics, 2011). However, loss of both Dnmt3a and -3b primarily resulted in loss of DNA methylation that was much more extensive than that seen in the 3a-KO. In addition, RNAseq of the mutant HSCs revealed increased expression of repetitive elements, inappropriate splicing, and truncation of 3ÕUTRs. To gain insight into the accumulation of Dnmt3ab-dKO HSCs in the bone marrow, we performed a time course analysis of the proliferation and apoptosis status of the HSCs. Every four weeks after transplantation of HSCs, we sacrificed a cohort of 3 control and 3 dKO mice, counted donor derived HSCs in the bone marrow, and analyzed their Ki67 and Annexin V expression. Up to 12 weeks post-transplant, no significant differences are seen in the expression of Ki67 or Annexin V. These data show that while Dnmt3b alone has minimal impact on DNA methylation in HSCs, Dnmt3a and -3b act synergistically to effect gene expression changes that permit HSC differentiation. In the absence of both of these de novo DNA methyltransferases, there is an immediate and extreme shift toward self-renewal of dKO HSCs. The Ki67 and Annexin V expression patterns suggest that a lack of de novo DNA methylation does not affect the proliferation or apoptosis of HSCs, but instead that the accumulation of HSCs and lack of peripheral blood contribution is primarily due to an imbalance between self-renewal and differentiation. By understanding the mechanisms through which Dnmt3a and -3b exert these effects, we should identify genes that are critical for normal hematopoietic differentiation. These genes may serve as targets for therapeutic intervention in malignancies caused by defective DNA methyltransferases. Figure 1: HSC composition of the bone marrow after secondary transplantation of control (left) and double Dnmt3a/3b KO (right) HSCs. After control HSC transplantation, HSCs comprise ∼0.01% of whole bone marrow. After transplantation of dKO HSCs, phenotypically-defined HSCs (KLS CD34–Flk2–) comprise ∼0.48% of bone marrow. Figure 1:. HSC composition of the bone marrow after secondary transplantation of control (left) and double Dnmt3a/3b KO (right) HSCs. After control HSC transplantation, HSCs comprise ∼0.01% of whole bone marrow. After transplantation of dKO HSCs, phenotypically-defined HSCs (KLS CD34–Flk2–) comprise ∼0.48% of bone marrow. Disclosures: No relevant conflicts of interest to declare.

Genomic Characterization Of Histiocytic Lesions Following Pediatric T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4940-4940
Author(s):  
Richard McMasters ◽  
Brian K. Turpin ◽  
Michael J. Absalon ◽  
Christine L. Phillips ◽  
Karen Burns ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Previous History ◽  
Genomic Analysis ◽  
High Dose ◽  
Pet Ct ◽  
History Of ◽  
Genomic Characterization ◽  
Notch1 Mutations

Abstract Introduction The development of histiocytic lesions after acute lymphoblastic leukemia (ALL) is rare, occurring in 6 of 971 patients enrolled on BFM treatment regimens for T-ALL (Trebo 2005).  Few cases of histiocytosis arising after a history of T-ALL have been characterized at the molecular level for genomic alterations. One case of fatal Langerhans cell histiocytosis (LCH) following treatment of T-ALL revealed activating mutations in NOTCH1; in contrast, no NOTCH1 mutations were identified in 24 other cases of LCH or Rosai-Dorfman disease without a previous history of T-ALL (Rodig 2008). In patients without prior leukemia, BRAF V600 mutations have been identified in a significant proportion of patients with LCH or Erdheim-Chester Disease but not in other histiocytoses (Haroche 2012). Methodology and Principal Findings Next generation focused exomic sequencing of 236 genes and 47 Introns was conducted on samples of histiocytic lesions from two patients with a previous history of T-ALL. Case 1 A 2 year-old male presented with marked adenopathy, mediastinal mass and white blood cell count 67,000 cells/uL with 30% blasts. The blasts expressed CD45, CD2, CD3 (surface/cyto), CD5, CD7, CD38, CD45 (bright), TCR gamma-delta, but were negative for CD4, CD8, and TdT.  Karyotype was 46,XY,t(8;14)(q24;q11.2),der(12)t(12;20)(q11;q13.3),der(20)t(12;20)(q21;q13.3) with rearrangement of MYC (8q24) confirmed by FISH. He was treated for T-ALL per Children’s Oncology Group (COG) protocol AALL0434 and had 5% residual bone marrow blasts at day 29 of induction. MRD-negative remission was ultimately achieved with high-dose cytarabine and methotrexate followed by consolidation with nelarabine.  He underwent matched unrelated cord blood transplant following conditioning with cyclophosphamide and total body irradiation with cranial boost, and engrafted at day +14. Surveillance bone marrow at day +110 revealed systemic juvenile xanthogranuloma (JXG) without T-ALL. PET/CT revealed FDG-uptake in the diffusely enlarged spleen and throughout the skeleton. Due to progressive cytopenias, therapy was initiated with vinblastine and prednisone as per LCHIII. However, refractory cytopenias exacerbated by splenic sequestration developed following induction, and he was then treated with thalidomide and splenectomy. The spleen weighed 404 grams (expected 40 grams) and was diffusely infiltrated with JXG. The cytopenias dramatically improved and he continued thalidomide for 2 months until PET scan demonstrated progression. Genomic analysis of the JXG lesion revealed NRAS G13D mutation, and FISH demonstrated MYC rearrangement identical to the initial T-ALL sample. Case 2 A 12-year-old male presented with WBC 142,700 cells/uL and CNS leukemia. Flow cytometry showed T-ALL with CD2, surface CD3, CD4, CD5, CD7, CD8, CD24 (subset), CD71, HLA-DR (subset) and TdT (partial). There was a clonal TCR gamma gene rearrangement and a biallelic CDKN2A (p16) deletion by FISH. He was enrolled on COG AALL0434 and had a rapid response with remission in both CNS and marrow at induction day 29.  Following completion of high-dose methotrexate interim maintenance he developed hepatosplenomegaly, pancytopenia and elevated serum bilirubin, ferritin, and triglycerides.  Bone marrow aspirate showed rare hemophagocytosis but no evidence of T-ALL.  He was treated with dexamethasone and etoposide with no response. Follow-up bone marrow revealed brisk hemophagocytosis and a diffuse histiocytic neoplasm. Karyotype was 48,XY,+7,+11[2] /49,idem,+18[3] /46,XY[14]. PET/CT showed hepatosplenomegaly with FDG uptake in anterior mediastinum, hepatic nodules, spleen, and bone marrow. He was treated with Campath and then with intensive chemotherapy with fludarabine, cytarabine, and liposomal daunorubicin with no response and ultimately succumbed to disease. Genomic analysis of the clonal histiocytic infiltrate revealed KRAS G12C, BRAF G469V, NOTCH1 Q2440, and CCND2 G268R mutations, and FISH positive for biallelic CDKN2A (p16) deletion similar to original T-ALL. Conclusions Our extensive genomic characterization suggests a unique molecular pathogenesis for histiocytic disorders arising after T-cell ALL and identified RAS signaling pathway and NOTCH1 mutations. Furthermore, these findings strongly indicate a potential derivation or trans differentiation from the malignant leukemic stem cell clone. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical implications of globally emerging azole resistance in Aspergillus fumigatus

2016 ◽  
Vol 371 (1709) ◽  
pp. 20150460 ◽  
Author(s):  
Jacques F. Meis ◽  
Anuradha Chowdhary ◽  
Johanna L. Rhodes ◽  
Matthew C. Fisher ◽  
Paul E. Verweij
Keyword(s):  
De Novo ◽  
Animal Health ◽  
Treatment Options ◽  
Previous History ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Cross Resistance ◽  
Azole Resistance ◽  
Health Food ◽  
History Of

Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus . However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium , Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR 34 /L98H, TR 53 and TR 46 /Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.

scholarly journals ACUTE HEART FAILURE

2018 ◽  
Vol 25 (09) ◽  
pp. 1392-1396
Author(s):  
Jasia Reham Din ◽  
Shahid Maqbool ◽  
Shakeel ur Rehman ◽  
Naeem Hameed
Keyword(s):  
Heart Failure ◽  
Acute Heart Failure ◽  
De Novo ◽  
Past History ◽  
Previous History ◽  
Young Male ◽  
Uncontrolled Hypertension ◽  
Cross Sectional ◽  
History Of ◽  
Emergency Department Patients

Objectives: To determine the frequency of the major precipitating factorsamong the patients presenting with acute heart failure. Study Design: Cross sectional study.Setting: Faisalabad Institute of Cardiology, Faisalabad. Period: July 2014 to January 2015.Materials and Methods: 190 patients of acute heart failure were included after obtaininginformed consent from emergency department. Patients from age of 25 years to 80 years andof either sex either diabetic or non-diabetic were enrolled in study. ECG and CXR were takenin emergency with baseline investigations. Precipitating cause was identified from collectedhistory, clinical examination and ECG, CXR and lab results. Results: Mean age of these patientswere 54.4 + 8.92, 100 (52.6%) were male, 90 (47.4%) were females, 88 patients (46.3%) werediabetic, 102 patients (53.68%) were non-diabetic and 124 (65.3%) had previous history of heartfailure and 66 (34.7%) had no past history of heart failure. ACS was the common precipitatingfactor of Acute Heart Failure ( 31.57% ) among all the patients of the study with non-complianceof drugs 27.9% , arrhythmias 17.9% uncontrolled hypertension 17.36% and infections 5.3%.Conclusion: Young, male, diabetics and patients with history of chronic HF suffered more fromAHF. ACS was the most common precipitating factor while in patients with de novo Acute HeartFailure; it was ACS and non-compliance with drugs.

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