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  • 1
    In: Blood, American Society of Hematology, Vol. 99, No. 6 ( 2002-03-15), p. 2032-2036
    Abstract: CCAAT/enhancer-binding proteins (C/EBPs) are critical transcriptional regulators of differentiation of hematopoietic cells. Previous studies have shown that targeted disruption of theC/ebpα gene results in a lack of granulocytic differentiation with an arrest at the stage of immature myeloblasts. By using a gene replacement strategy in which C/EBPβ was expressed from the C/ebpα gene locus of C/EBPα-null mice, we have evaluated the ability of C/EBPβ to function for C/EBPα in directing differentiation along the granulocytic pathway. We show that the morphology and the differential cell counts of the bone marrow and peripheral blood cells from C/EBPβ knockin mice are indistinguishable from those of their wild-type littermates, indicating that hematopoiesis occurs normally in these animals. Additionally, we analyzed expression of 21 myeloid-specific genes, including markers for distinct stages of granulocytic differentiation, and found no significant differences in their levels of expression in the bone marrow of C/EBPβ knockin and wild-type mice. These results imply that C/EBPβ can substitute for C/EBPα during hematopoiesis when expressed from the C/ebpα gene locus.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2002
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  • 2
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 485-485
    Abstract: Abstract 485 In order to assess the relative value of major treatment variables for AML and subgroups in a representative setting 2693 patients were treated in a multicenter trial. To avoid a selection during treatment and to provide intention-to-treat conditions in a factorial design patients were randomized up-front in one step to receive TAD-HAM versus HAM-HAM induction, G-CSF priming with all chemotherapy courses during the 1st year versus no G-CSF, and for postremission therapy TAD consolidation followed by monthly myelosuppressive maintenance versus autologous stem cell transplantation instead of maintenance (TAD, thioguanine, araC standard dose and daunorubicin; HAM, araC 3 (age 〈 60) or 1 (age 60+) g/m2 × 6 with mitoxantrone; G-CSF 150μg/m2/day from 48h before until the end of the chemotherapy course; maintenance, 5-day standard dose araC with daunorubicin or with thioguanine or with cyclophosphamide alternatingly). The median age was 61 (range 16-85) years with 55% of patients 60 years or older, 27% patients had AML secondary to cytotoxic treatment or myelodysplasia. Favorable, intermediate, and unfavorable cytogenetics were found in 7.5%, 67% and 25.5% of patients, respectively. Among 956 patients with normal cytogenetics the mutation status was availabel with NPM1 mut/ FLT3-ITD neg in 33% and other combinations in 67%. The median observation time for the entire patients was 4.4 years . In the patients 〈 60 years the overall survival (OS) at 5 years is 40%. 65% went into complete remission (CR). Their relapse rate (RR) at 5 years is 52%. Patients of 60+years show an OS of 13% at 5 years, a CR rate of 54%, and a RR of 81% at 5 years. There were no significant differences in these parameters with respect to randomizations between TAD-HAM versus HAM-HAM, G-CSF priming versus no G-CSF, maintenance versus autologous stem cell transplantation. In a multivariate analysis including all patients and ages the main determinants of OS were age 60+y (HR 2.00; 95% CI 1.82-2.21), de-novo AML (0.79; 0.71-0.88), unfavorable karyotype (2.05; 1.84-2.28), favorable karyotype (0.47; 0.37-0.60), day 16 b.m. blast clearance (0.66; 0.61-0.74), and LDH (1.36; 1.19-1.54). Corresponding factors for the RR were age 60+ (1.90; 1.65-2.18), unfavorable karyotype (1.83; 1.54-2.17), favorable karyotype (0.41; 0.30-0.55), LDH (1.33; 1.11-1.59), and day 16 b.m. blast clearance (0.79; 0.68-0.93). In patients with normal karyotype the main determinants of OS were age 60+ (2.12; 1.77-2.54), NPM1mut/ FLT3-ITD neg (0.45; 0.36-0.56), and for the RR age 60+ (1.87; 1.49-2.35), and NPM1mut/ FLT3-ITD neg (0.37; 0.29-0.48). Even in patients 〈 60 years age older than the median (47y) is a major risk factor for OS (1.56; 1.33-1.82) and RR (1.35; 1.10-1.66). Conclusion: In a prospective analysis of representative and unselected patients with AML the outcome of therapy is mainly determined by chromosomal and molecular abnormalities and by older age as an own risk factor. The influence of treatment variables such as substantial increase in high-dose araC, G-CSF priming, or autologous SCT is neglectable. Present data may contribute a basis for novel molecular and immunologic approaches. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 425-425
    Abstract: Abstract 425 The introduction of all-trans-retinoic acid (ATRA) in front line therapy of acute promyelocytic leukemia (APL) has improved the outcome of all age groups. In the elderly patients (pts), multi-morbidity and higher vulnerability to chemotherapy-related toxicity are the main problems reducing the chance of cure. This has led to recommendations to reduce the intensity of therapy in elderly APL pts. We report on the long-term outcome of pts with newly diagnosed APL registered in two prospective studies of the German AML Cooperative Group (AMLCG) from December 1994 until June 2011. The therapy consisted of ATRA and anthracycline/ara-C-based induction and consolidation therapy (TAD/HAM–TAD) followed by maintenance therapy as reported previously in younger APL pts (Lengfelder et al. Leukemia 2009;23:2248–2258). In pts ≥60 years (y), the administration of the second induction cycle (HAM with an age adapted cumulative ara-C dose of 6g/sqm) was at the discretion of the treating physician. After December 2005, the pts were included in the ongoing APL protocol and randomized between the AMLCG strategy and the protocols of the Spanish PETHEMA. Among 295 adult pts with newly diagnosed APL, 83 pts (28%) were ≥60y of age. Seventeen elderly pts (20%) were not enrolled in the study, due to death before start of therapy, contraindications against chemotherapy or concomitant other malignancy. Eleven pts randomized in the PETHEMA arm were excluded from the present analysis to cover homogeneity of therapy. In 53 of 55 pts treated according to the AMLCG protocol, results are available. Median age was 67 y (range 60 to 83); 58% were male, 42% female; 68% had low/intermediate and 32% high risk according to Sanz score. Morphology was FAB M3 in 62%, M3v in 38%. Cytogenetics showed t(15;17) alone in 52%, and combination with other abnormalities in 48% of pts. The bcr1/bcr2 transcript of PML/RARA was found in 41% and the bcr3 transcript in 59% of pts. Forty-four pts (83%) achieved complete remission (CR). Early death (ED) occurred in 9 pts (17%). Median time to ED was 12 days (range 2 to 19) after start of therapy. Causes of ED were bleeding, multi-organ failure and sepsis. Manifest APL differentiation syndrome occurred in 25% of pts and WHO grade '3 bleeding, fever/infection or cardiac failure in 8%, 43% and 17% of pts, respectively. After consolidation therapy, 96% of pts were in molecular remission. After a median follow up of 5.3 y (1 day to 12.8 y), the 6-year overall (OS), event free (EFS) and relapse free survival (RFS) and the cumulative incidence of relapse (CIR) were 45%, 41%, 50% and 26%, respectively. The outcome was further analyzed according to risk group, number of induction cycles, and age ≥60y to 69y and ≥70y. Pts with pretreatment white blood cell (WBC) count 〈 10 × 109/L (low/intermediate risk; n=36) had a significantly superior outcome compared to pts with high WBC counts (high risk; n=17) resulting in a CR rate of 92% vs. 65% and ED rate of 8% vs. 35%, respectively (p=0.02). The 6-year OS, EFS, RFS and CIR of the low/intermediate risk pts was 56%, 53%, 60% and 14%, respectively, compared to 25%, 15%, 23% and 58% in high risk pts (p=0.006, p=0.0004; p=0.008; p 〈 0.01). All 12 pts, who had received two induction cycles achieved CR, and no relapse occurred so far resulting in a significantly superior outcome compared to patients, who had received only one induction cycle (OS: p=0.007; EFS: p=0.0002; RFS: p=0.01). In the pts '70y (n=17), 71% entered CR and 29% died from ED. Separated according to low and high WBC counts, the CR rate of this group was 83% vs. 40% and the ED rate 17% vs. 60% (p=0.07), respectively, resulting in an inferior OS (p=0.08) of the pts with high WBC count. Conclusions: Among our elderly pts, we found a high proportion of pts with high risk profile and a high rate of exclusion from the study due to death before the start of therapy or poor condition. In patients included in our study, high WBC count and advanced age are associated with a high risk of ED. The inferior outcome in pts, who received only one induction cycle, suggests that intensification of chemotherapy should be considered in elderly APL pts, if possible. The incorporation of arsenic trioxide might be an alternative, which could be investigated in future trials. Disclosures: No relevant conflicts of interest to declare.
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    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 335-335
    Abstract: Abstract 335 Purpose. Standard chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival of only 〈 /= 1 year. Considerable numbers of elderly patients with AML present with cardiac comorbidity rendering the use of daunorubicin (DNR) containing chemotherapy regimens hazardous. Gemtuzumab ozogamicin (GO) is active in elderly (=/ 〉 60 years) patients with relapsed AML and shows low cardiac toxicity. The purpose of the randomized phase II study reported here was to compare the antileukemic activity of a standard combination of ara-C (100 mg/m2/day c.i., days 1–7) and DNR (60 mg/m2 i.v., on days 3–5) (7+3) versus ara-C plus GO (6 mg/m2 i.v. on days 1 and 8) (7+GO) as the first course of induction therapy in AML patients at the age of 60 years and older. Patients and Methods. On the basis of the data from the AMLCG (JCO 27: 61–69, 2009) the study was powered to detect an increase of median event free survival (EFS) from 90 to 160 days and a prolongation of the median overall survival (OS) from 9 to 〉 16 months with a power of 80% (alpha= .05), in order to obtain information as a basis for potential further phase III randomized studies. Primary objectives of the study were the achievement of blast clearance ( 〈 5%) on day 16 after induction therapy onset and EFS. OS, complete response (CR) and tolerability were among the secondary objectives. 112 pts. entered the study, suffering from de novo AML, treatment-related secondary AML, AML with a history of MDS, and high-risk MDS. Median age of the patients was 69 years (range 60–83). Study protocol outlined a second induction course 7+3 in those pts. without blast clearance on day 16 and 2 courses of consolidation therapy with high-dose ara-C (1 g/m2 q 12 hours i.v., days 1, 3, 5) for patients in CR. We looked for balance of AML standard risk factors between both arms of the study. Results. The study was approved by the Ethical Board of the University of Muenster and the other participating institutions and written informed consent was obligatory by every pt. prior to entry on study. 58 pts. were randomized to induction therapy with 7+3 as the first course, whereas 54 pts. were randomized to receive 7+GO. All parameters evaluated are for the intent-to-treat population. There were no statistically significant differences between treatment arms in blast clearance ( 〈 5%) on day 16 after treatment onset (7+3: 18 pts., 7+GO: 19 pts.), complete response (CR) rate (7+3: 53.5%, 7+GO: 61.1%), EFS (median for 7+3: 67 days, median for 7+GO: 172 days), or OS (median for 7+3: 9 months, median for 7+GO: 15 months). Toxicity profiles of the protocols were different with 4 pts. developing severe veno-occlusive disease in the 7+GO group. Conclusion. The study did not show a significant advantage of 7+GO over 7+3 as the first course of induction treatment in elderly pts. with AML. Ara-C and GO and ara-C and DNR have comparable antileukemic activity as the first course of induction. Ara-C and GO may represent an alternative, replacing non-targeted anthracyclines for induction therapy of elderly AML patients e.g. with significant cardiac comorbidities. Disclosures: Berdel: Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Mylotarg as first-line treatment in AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 5
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 327-327
    Abstract: Abstract 327 Introduction: Older patients (≥ 60 years) with acute myeloid leukemia (AML) display a dismal prognosis with only half of the patients reaching a complete remission after intensive induction therapy. The decision whether or not to use intensive chemotherapy is often difficult given the limited number of known markers that might predict the chance to achieve a complete remission. The aim of this study was to establish a risk score for therapy-failure based on clinical variables for older but medically fit AML patients. Patients and Methods: 1379 patients ≥ 60 years of age with AML evaluable for an induction result after treatment with an intensive induction regimen (randomized standard-dose cytarabine containing TAD or high-dose cytarabine (1g/sqm × 6) containing HAM, with a second induction course HAM in case of blast persistence after the first course) within the AMLCG1999 study of the German AML Co-operative Group were evaluated. The following parameters were evaluated for risk prediction in an exploratory analysis: Age, sex, de novo versus secondary leukemia, performance status, body mass index, body temperature, presence of extramedullary manifestations, spleen size, presence of lymph node enlargement, hemoglobin, peripheral blood leukocytes, platelets, blast percentage in peripheral blood and bone marrow, total protein in serum, alanine aminotransferase (ALT), alkaline phosphatase (AP), bilirubin, lactate dehydrogenase (LDH), FAB classification, prothrombin time (PT) and fibrinogen. Since cytogenetics and molecular markers are often not available at the time of decision making, these data were not included. Results: Within this cohort of patients, 744 (54 %) achieved a complete remission. Among the analyzed parameters, age, de novo versus secondary leukaemia, body mass index, body temperature, hemoglobin, peripheral blood leukocytes, platelets, bone marrow and peripheral blood blasts, ALT, AP, LDH, PT and fibrinogen were significantly associated with a CR (p 〈 0.05) in a univariate log rank analysis. In a multivariate logistic regression model, the following parameters retained its significance: age (60 – 63 years, 64 – 67 years, 68 – 72 years, ≥ 73 years) de novo versus secondary leukemia, body temperature (≤ 36°C, 〉 36°C – 38°C, 〉 38°C), hemoglobin (≤ 10.3 g/dl versus 〉 10.3 g/dl), platelets (≤ 28,000, 〉 28,000 - 53000, 〉 53,000 – 103,000, 〉 103,000 per μl), AP (≤ 89 U/l versus 〉 89 U/l), PT (≤ 75 %, 〉 75 – 87 %, 〉 87 – 98 %, 〉 98 %) and fibrinogen (≤ 150 mg/dl versus 〉 150 mg/dl). Based on these parameters, the predicted remission rates were: minimum, 18.3 %; 1st quartile, 43.9 %; median, 54.4 %;3rd quartile, 64.3 %; maximum: 88.1 %. The observed remission rates were: 1st quarter, 35.7 %; 2nd quarter, 50.3 %; 3rd quarter, 60.2 %; 4th quarter, 69.8 %. Conclusions: Taken together, this risk prediction score based on pre-treatment values predicted the remission probability in patients ≥ 60 years of age with AML receiving an intensive induction therapy. This score may be useful for the determination of the therapy strategy in elderly patients with AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1280-1280
    Abstract: Abstract 1280 Poster Board I-302 Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are defined as clonal hematopoietic stem cell disorders. These disorders show an inherent tendency for transformation into leukemia (MPN-blast phase) which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, obtained a comprehensive profile of genomic alterations associated with leukemic transformation by using single-nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. A relatively high number of genomic alterations was found in MPN after leukemic transformation with 4.6 ± 0.6 abnormalities per sample compared to only 1.4 ± 0.2 changes per patient in chronic phase (p 〈 0.001). Compared to the cytogenetic data, SNP-chip analysis detected about 47% additional chromosomal changes in the MPN samples, and 31% more in the MPN-blast phase cases, whereas SNP-array allelokaryotyping practically captured all cytogenetic abnormalities in our study population. Several additionally altered regions were detected in patients with MPN-blast phase compared to chronic phase, including both deletion and copy-number neutral-loss of heterozygosity (CNN-LOH) on chromosome 12p (9%) and 21q (9%), involving ETV6 and RUNX1. Notably, deletion and CNN-LOH on 17p involving TP53 were diagnosed in 18% of MPN-blast phase samples, which was highly associated with preceding treatment with alkylating agents (p=0.016). Moreover, trisomy 8, as well as amplification of 8q24.21 involving the MYC gene, were detected in 13% of patients with MPN-blast phase who were almost exclusively negative for the JAK2V617F mutation. Genome-wide inspection of further critical regions with promising new candidate genes involved in the evolution to the MPN-leukemic phase included deletion and CNN-LOH on 7q22.1 (SH2B2) in 18%, duplication/amplification on 19p13.2 (PIN1, ICAM1, CDC37) in 13% and 21q22.2 (ERG) in 9% of MPN patients with blast crisis. In contrast, we detected a decreased frequency of JAK2V617F in MPN-blast phase samples (52%) compared to chronic phase (71%). Also, the percentage of patients with homozygous mutant JAK2 as a result of CNN-LOH was lower in the MPN-blast phase (43%) compared to the chronic phase (53%). Taken together, the data suggest that gain-of-function mutation of JAK2 is not a perquisite for leukemic transformation. Remarkably, CNN-LOH on either 7q or 9p was related to decreased survival after leukemic transformation (p=0.02 and p=0.012, respectively). Given the variety of allelic imbalances, our data suggest that MPN-blast phase appears to be a heterogeneous disease prone to have evolved multiple mechanisms to provide a proliferative advantage to the abnormal leukemic clone. Our analysis of MPN genomes in the chronic compared to the leukemic stage provided new prognostic insights, as well as novel causative genes which might be involved in the transformation to MPN-blast phase. Disclosures No relevant conflicts of interest to declare.
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    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1974-1974
    Abstract: Abstract 1974 Most available data on the relative value of allogeneic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) in first complete remission (CR1) in the past, were generated from donor versus no-donor comparisons, focusing on documented tissue-typed patients and their siblings. The inclusion of patients who are not HLA-typed, for instance all those without siblings, causes bias of unknown magnitude. Additionally, concerns about the equivalence of related and unrelated donors should no longer be a problem in contemporary evaluation of allo-SCT. Using data of the prospective AMLCG 1999 trial, we performed a matched-pair analysis, to evaluate outcome in patients with AML according to post-remission allo-SCT or conventional postremission chemotherapy (PRT). 165 patients pairs in CR1 were identified, who matched for the following criteria: AML type (de novo AML, s-AML, t-AML, high-risk MDS); cytogenetic risk group [unfavorable (UNF-CG), intermediate (INT-CG), and favorable with the exclusion of t(15;17)]; age (± 5 years); and time in CR1 to account for the time to transplant in allo-SCT patients. If possible, patients were also matched for sex and assigned induction treatment (TAD-HAM versus HAM-HAM). 34 patient pairs had an UNF-CG, 122 pairs INT-CG, and 9 pairs had favorable cytogenetics. Median patients age at diagnosis was 45 years (range: 16–59). In the allo-SCT cohort, 105 patients had a related donor (matched related donor [MRD] 104, haploidentical 1) and 60 a matched unrelated donor (MUD). Median follow-up of surviving patients after first diagnosis of CR1 was 7.5 years. Projected 7-year relapse-free survival (RFS) was 56% in the allo-SCT group and 39% in the control group (p 〈 .0001, log-rank test). Overall survival (OS) was 58% and 45% (p=.143), respectively. RFS was significantly improved by allo-SCT in patients with UNF-CG (23% vs. 12% at 7 years; p=.005) or INT-CG (58% vs. 37%; p=.001). OS was 31% in allo-SCT patients with UNF-CG versus 18% in matched controls (p=.052) and 64% in INT-CG patients with allo-SCT versus 54% in matched controls (p=.403). Dividing the 330 patients into age groups by decades, revealed an age dependent, increasing risk of relapse for patients receiving conventional post-remission therapy, with cumulative relapse incidences of 51% ( 〈 31 years), 47% (31–40 years), 60% (41–50%) and 87% (51–60 years) at 7 years, whereas allo-SCT patients had similar relapse incidences of 32%, 34%, 25% and 34% respectively. The higher relapse incidence in control patients 〉 50 years of age, resulted in a significantly better OS of allo-SCT patients with 27% versus 58% (p=.022) in this age group. In the subset of patients with INT-CG, allo-SCT patients with non-normal karyotype had both a significant better OS and RFS after 7 years compared to control patients, whereas patients with normal karyotype had similar RFS and OS regardless of NPM1 and FLT3 mutational status. Of note, 48 of 99 patients with AML relapse in the control cohort, received an allo-SCT (18 from a MRD, 30 from a MUD) beyond CR1 (9 with UNF-CG, 38 with INT-CG, 1 with favorable CG). Median OS of 48 matched patients receiving an allo-SCT in CR1 was 54%, while it was 39% in paired patients with allo-SCT beyond CR1 (p=.289). We conclude that allo-SCT is the most potent post-remission therapy for AML with UNF-CG and INT-CG. Its impact on OS is difficult to assess, as about a third of patients initially treated with conventional PRT, underwent allo-SCT beyond CR1. In contrast to results from donor versus no-donor comparisons, our data highly suggest a benefit of allo-SCT in CR1, particularly for elderly patients, and in line with such comparisons, for patients with intermediate-II (according to the European LeukemiaNet [ELN] recommendation) or unfavorable ELN cytogenetic risk. Ultimately, the gold standard for the evaluation of allo-SCT in patients with INT-CG in CR1 is a randomized controlled trial, which is now feasible with unrelated donors becoming w idely available and is conducted by the German Cooperative Transplant Study Group (ETAL-1 study). Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 690-691
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 9
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 3338-3340
    Type of Medium: Online Resource
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 10
    In: Blood, American Society of Hematology, Vol. 99, No. 4 ( 2002-02-15), p. 1332-1340
    Abstract: The CCAAT/enhancer binding protein α (C/EBPα) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBPα function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBPα gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4. The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2 and AML-M4) samples. Some mutations truncated the predicted protein with loss of the DNA-binding (basic region) and dimerization (leucine zipper [ZIP]) domains by either deletions or nonsense codons. Also, inframe deletions or insertions in the fork region located between the leucine zipper and basic region, or within the leucine zipper, disrupted the α-helical phase of the bZIP domain. The inframe deletion and insertion mutations abrogated the transcriptional activation function of C/EBPα on the granulocyte colony-stimulating factor receptor promoter. These mutants localized properly to the nucleus, but were unable to bind to the C/EBP site in the promoter and did not possess dominant-negative activity. The mutations in the MDS patient and one AML-M2 patient were biallelic, indicating a loss of C/EBPα function. These results suggest that mutation of C/EBPα is involved in specific subtypes of AML and in MDS, but may occur rarely in other types of leukemias or nonhematologic malignancies.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2002
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