National Cancer Institute®
Last Modified: September 1, 2002
UI - 12105272
AU - Schoch C; Kohlmann A; Schnittger S; Brors B; Dugas M; Mergenthaler S;
TI - Kern W; Hiddemann W; Eils R; Haferlach T Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles.
SO - Proc Natl Acad Sci U S A 2002 Jul 23;99(15):10008-13
AD - Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, 81366 Munich, Germany. firstname.lastname@example.org
Acute myeloid leukemia (AML) is a heterogeneous group of genetically defined diseases. Their classification is important with regard to prognosis and treatment. We performed microarray analyses for gene expression profiling on bone marrow samples of 37 patients with newly diagnosed AML. All cases had either of the distinct subtypes AML M2 with t(8;21), AML M3 or M3v with t(15;17), or AML M4eo with inv(16). Diagnosis was established by cytomorphology, cytogenetics, fluorescence in situ hybridization, and reverse transcriptase-PCR in every sample. By using two different strategies for microarray data analyses, this study revealed a unique correlation between AML-specific cytogenetic aberrations and gene expression profiles.
UI - 12145461
AU - Kitamura N; Koshiba M; Horie O; Ryo R
TI - Expression of granulysin mRNA in the human megakaryoblastic leukemia cell line CMK.
SO - Acta Haematol 2002;108(1):13-8
AD - Department of Medical Technology, Faculty of Health Sciences, Kobe University School of Medicine, Kobe, Japan.
Granulysin is a newly reported cytolytic molecule and colocalizes with perforin and granzymes in the granules of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. In this study, we found that the megakaryoblastic leukemia cell line CMK, established from a patient with Down's syndrome, expressed granulysin mRNA. CMK was positive for CD13 and CD41 and negative for CD56. CMK also expressed CD2 and CD7. However, no rearrangement of the T-cell receptor beta-chain gene, an early marker of T-cell lineage, was found in CMK cells. Thus, CMK is assumed to originate from the clonal evolution at the immature cell level. The expression of granulysin in CMK cells suggests that granulysin is occasionally present in immature multilineage cells or may be characteristic of leukemic cells obtained from Down's syndrome patients. CMK has been reported to be capable of differentiating to mature megakaryocytes and produce platelets with normal function. It therefore seems to be possible that granulysin is also present in normal platelets. Unfortunately, we were not able to obtain evidence that normal platelets contain granulysin mRNA and its antigen. Copyright 2002 S. Karger AG, Basel
UI - 7514246
AU - Flasshove M; Strumberg D; Ayscue L; Mitchell BS; Tirier C; Heit W;
TI - Seeber S; Schutte J Structural analysis of the deoxycytidine kinase gene in patients with acute myeloid leukemia and resistance to cytosine arabinoside.
SO - Leukemia 1994 May;8(5):780-5
AD - Innere Klinik und Poliklinik (Tumorforschung) Universitatsklinikum Essen, Westdeutsches Tumorzentrum Essen, Germany.
Deficiency of deoxycytidine kinase (dCK) activity represents one possible cause of resistance to cytosine arabinoside (ara-C). Mutations of the dCK gene have recently been shown to be responsible for dCK deficiency and increased resistance in vitro. In order to define the relevance of this mechanism in vivo, we analyzed the dCK gene in 16 adult patients with relapsed/refractory acute myeloid leukemia (AML) and clinical resistance to standard-dose and/or high-dose ara-C. Southern blot analysis using genomic DNA from peripheral blood or bone marrow samples containing > or = 70% leukemic blasts and agarose gel electrophoresis of cDNA obtained by RT-PCR did not reveal gross rearrangements of the dCK gene. Sequencing of the dCK coding region showed point mutations in seven patients. Besides two silent mutations (or RFLPs) in codon 42 and 86, base pair mutations resulting in amino acid replacements were found in five patients affecting codon 20, 93, 98, 99, and 154, respectively. dCK cDNA clones from three patients with > or = 50% of sequenced clones revealing the specific base pair alteration were bacterially expressed in E. coli and analyzed for dCK activity. Normal enzyme activity was found in two patients (codon 20 and 98), and a complete loss of activity in one patient (codon 99). We conclude that structural alteration of the coding region of the dCK gene represents one possible mechanism for ara-C resistance in vivo, but, considering the frequency of this event, other mechanisms may play a more important role for clinical resistance to ara-C in patients with AML.
UI - 11901667
AU - Speer SA; Semenza JC; Kurosaki T; Anton-Culver H
TI - Risk factors for acute myeloid leukemia and multiple myeloma: a combination of GIS and case-control studies.
SO - J Environ Health 2002 Mar;64(7):9-16; quiz 35-6
AD - Epidemiology Division, Department of Medicine, University of California, Irvine, 224 Irvine Hall, Irvine, CA 92697-7550, USA.
Risk factors for acute myeloid leukemia (AML) and multiple myeloma (MM) include exposure to toxic chemicals present in tobacco smoke, as well as to emissions from industrial operations and petroleum refinery waste dumps. The study reported here identified these risk factors among case patients and control patients in Orange County, California, from 1984 to 1993 and determined the significance of the risk factors in the study population. A case-control study was performed for 604 cases of AML and 643 cases of MM; there were 7,112 control subjects who had colon cancer. The model included the variables smoking history, occupational history, and residence in a census tract with a petroleum refinery waste dump. A geographic information system (GIS) analysis also was performed to correlate the incidence of AML and MM with proximity to the six dump sites that received large amounts of petroleum refinery waste. Current smokers were found to be at an increased risk of AML with an odds ratio of 2.0. Laborer/equipment cleaners and transportation workers/movers were at risk of AML with odds ratios of 3.5 and 2.4, respectively. Construction/resource extraction workers were at risk of MM with an odds ratio of 2.8. GIS analysis determined that the risk for MM was 1.6 cases per mile for 10 or more years of residence near a large chemical dump. The authors were able to identify census tracts with a high incidence of AML and MM, and to perform distance analysis using a statistical measure of spatial randomness. The case-control study identified occupational and lifestyle risk factors for AML and MM that were not apparent from census-tract-level data.
UI - 12150726
AU - Chen H; Wu S
TI - Hypermethylation of the p15(INK4B) gene in acute leukemia and myelodysplastic syndromes.
SO - Chin Med J (Engl) 2002 Jul;115(7):987-90
AD - Department of Hematology, First Hospital of Peking University, Beijing 100034, China.
OBJECTIVE: To detect the methylation pattern of the p15(INK4B) gene and to explore its significance in the pathogenesis of acute leukemia (AL) and leukemic transformation of myelodysplastic syndromes (MDS). METHODS: A total of 49 AL cases and 22 MDS cases were analyzed by methylation specific polymerase chain reaction (MSP) for methylation patterns in CpG islands of the p15(INK4B) gene. RESULTS: Hypermethylation of the p15(INK4B) gene was found in 90% (26/29) of newly diagnosed AL, including 46% with complete methylation and 54% with partial methylation. All 3 evolved AL from MDS and 9 relapsed AL showed a methylated p15(INK4B) gene and the proportion of complete methylation was 67% and 56% respectively. Only 5 of 11 (45%) AL in remission, including 2 in complete remission (CR) and 3 in partial remission (PR), were partially methylated. The frequency of p15(INK4B) gene methylation in newly diagnosed or relapsed AL was significantly higher than that in AL in the remission stage (P = 0.002) p15(INK4B) gene methylation was found in 5 of 13 (38%) low-risk MDS (RA/RAS) patients and 80% of them showed only partial methylation. However, p15(INK4B) gene methylation was found in all 9 cases in the high-risk group (RAEB/RAEB-T), including complete methylation in 56%, significantly different from the low-risk MDS group (P = 0.002). CONCLUSIONS: Hypermethylation of the p15(INK4B) gene occurs frequently in leukemia and high-risk MDS. It is possible that hypermethylation of this gene is related to the pathogenesis and development of AL and MDS. It may be used as a gene marker to detect minimal residual disease, relapse of AL and leukemic transformation in MDS.
UI - 12187172
AU - Earle CC; Nattinger AB; Potosky AL; Lang K; Mallick R; Berger M; Warren
TI - JL Identifying cancer relapse using SEER-Medicare data.
SO - Med Care 2002 Aug;40(8 Suppl):IV-75-81
AD - Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. email@example.com
INTRODUCTION: Tumor registries capture valid information at the time of cancer diagnosis, but often do not conduct longitudinal follow-up evaluations. However, investigators may be interested in questions relating to subsequent relapsed disease. Linking administrative data to registry data, as in the creation of the SEER (Surveillance, Epidemiology, and End Results) and Medicare data set, can provide the ability to infer the occurrence of relapse in selected situations. METHODS: The authors created different algorithms to detect relapse of acute myelogenous leukemia (AML). A retrospective cohort of patients with AML was identified, and both their billing data and medical records were obtained. The algorithms were then applied to the billing data, the results were compared with medical record review. RESULTS: Eighty-nine patients were identified, of whom 22 were treated for relapsed AML. The sensitivity of the best algorithm for detecting relapse was 86%, and the specificity 99%, with a positive predictive value of 95% and a negative predictive value of 96%. CONCLUSIONS: Identification of relapse from SEER-Medicare data using clinical algorithms is feasible for cancers where a majority of patients receive treatment for relapse, without a "watch and wait" strategy, and where that treatment is with a modality that can be detected in billing data (ie, intravenous chemotherapy, radiation, surgery, or all three). Optimal analytic situations are ones in which the investigator is mostly interested in positive predictive value, less interested in sensitivity, and wants to evaluate outcomes among those patients who receive treatment for their relapsed disease. However, the accuracy of such an approach for cancers other than AML has not yet been established.
UI - 12211197
AU - Andersen MK; Pedersen-Bjergaard J
TI - Therapy-related MDS and AML in acute promyelocytic leukemia.
SO - Blood 2002 Sep 1;100(5):1928-9; discussion 1929
UI - 10500791
AU - Legrand O; Simonin G; Perrot JY; Zittoun R; Marie JP
TI - Both Pgp and MRP1 activities using calcein-AM contribute to drug resistance in AML.
SO - Adv Exp Med Biol 1999;457():161-75
AD - EA1529, Universite Paris VI, Formation de Recherche Claude Bernard, France.
Thirteen cell lines with different levels of Pgp and MRP1 expression were used to assess the ability of calcein-AM uptake and calcein efflux to measure Pgp and MRP1 functions, respectively. There was a good correlation between MRP1 expression and the modulatory effect of probenecid (a specific modulator of MRP1) on the calcein efflux (r = 0.91, p = 0.0003) and between Pgp expression and the modulatory effect of CsA on calcein-AM uptake (r = 0.96, p < 0.0001). On light of the high correlations for both proteins, we tested calcein-AM uptake and efflux in fresh myeloid leukemic cells. In 53 AML patients, there was also a good correlation between MRP1 expression (measured by RT/PCR and by MRPm6 expression by flow cytometry) and the modulatory effect of probenecid on the calcein fluorescence (r = 0.92, p < 0.0001) and between Pgp expression as measured by UIC2 antibody binding on flow cytometry and the modulatory effect of CsA on calcein-AM uptake (r = 0.83, p < 0.0001). Pgp activity was higher in CD34+ leukemia than in CD34- leukemia (2.26 +/- 1.50 vs 1.46 +/- 1.21 respectively, p = 0.003) and MRP1 activity was higher in CD34- leukemia than in CD34+ leukemia (1.77 +/- 0.40 vs 1.4 +/- 0.29 respectively, p = 0.004). Pgp expression and activity (p = 0.004 and p = 0.01, respectively), MRP1 activity (p = 0.03) but not MRP1 expression were prognostic factors for achievement of CR. The effect of probenecid and CsA together were higher than the effect of either probenecid or CsA alone on calcein-AM uptake. These results suggest that functional testing (with calcein-AM +/- modulators) for the presence of both MRP1 and Pgp activities is of prognostic value and that MRP1 contributes to drug resistance in AML.
UI - 11403708
AU - Nakanishi M; Tanaka K; Takahashi T; Kyo T; Dohy H; Fujiwara M; Kamada N
TI - Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors.
SO - Int J Radiat Biol 2001 Jun;77(6):687-94
AD - Department of Cancer Cytogenetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi l-2-3, Minami-ku, Hiroshima 734-8553, Japan.
PURPOSE: Genetic alterations, including microsatellite instability (MSI), are ultimate steps toward malignant process. To investigate MSI in A-bomb survivors, leukaemic cells were analysed from 13 acute myelocytic leukaemia patients with a history of radiation exposure and also in 12 de novo patients. MATERIALS AND METHODS: To assess the microsatellite changes, a fluorescent system in 10 loci (BAT40, D3S643, D5S107, IRF1, MYC, D9S171, WT1, TP53, DM, D17S855) was used. RESULTS: MSI analysis revealed a high frequency of multiple microsatellite changes in the exposed patients (84.6%) compared with non-exposed patients (8.3%). There was a significant difference (p < 0.001) between the two groups. CONCLUSIONS: These analyses clearly demonstrate that leukaemic cells from heavily exposed patients contain a number of genetic instabilities that may strongly influence the development of leukaemia among people exposed to the Hiroshima A-bomb radiation.
UI - 11794699
AU - Yamada S; Hongo T; Okada S; Watanabe C; Fujii Y; Hori H; Yazaki M;
TI - Hanada R; Horikoshi Y Distinctive multidrug sensitivity and outcome of acute erythroblastic and megakaryoblastic leukemia in children with Down syndrome.
SO - Int J Hematol 2001 Dec;74(4):428-36
AD - Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
We assessed the in vitro chemosensitivity of acute erythroblastic and megakaryoblastic leukemia cells from children with Down syndrome (DS) compared to non-DS children. We conducted in vitro tests using the MTT assay of bone marrow samples from 12 children with DS and 16 children without DS. Patients were newly diagnosed based on the morphology and expression of platelet-specific antigens. Induction failure occurred more frequently in the non-DS group (n = 4) than in the DS group (n = 0, P = .053). Children with DS had a superior event-free survival (EFS) probability of 0.750 at 4 years, compared to an EFS probability of 0.375 for non-DS children (P = .049). Blast cells from DS patients were significantly more sensitive to daunorubicin, melphalan, mitoxantrone, 4-hydroperoxy-cyclophosphamide, vincristine, etoposide, bleomycin, and pirarubicin than those from non-DS patients. Four of the 16 non-DS patients were found to have acquired an extra chromosome 21 in their leukemia cells: blasts from these patients also tended to have greater chemosensitivity than those from patients without an extra chromosome 21. Blast cells from DS patients are markedly sensitive to various drugs. These results suggest that the fragility of blast cells derived from DS patients may be related to an increased susceptibility to apoptosis.
UI - 12025826
AU - Cox R; Edwards AA
TI - Comments on the paper: Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors--and related cytogenic data.
SO - Int J Radiat Biol 2002 May;78(5):443-5
UI - 12123433
AU - Monge P; Wesseling C; Rodriguez AC; Cantor KP; Weiderpass E; Reutfors J;
TI - Ahlbom A; Partanen T Childhood leukaemia in Costa Rica, 1981-96.
SO - Paediatr Perinat Epidemiol 2002 Jul;16(3):210-8
AD - Central American Institute for Studies on Toxic Substances (IRET), Universidad Nacional, PO Box 86-3000, Heredia, Costa Rica. firstname.lastname@example.org
Childhood leukaemia incidence in Costa Rica during 1981-96, among the highest in the world, was analysed by histology, gender, birth year, time period of diagnosis, age at diagnosis and region. Numbers of cases were extracted from the database of the National Cancer Registry (RNT) of Costa Rica. Person-years at risk were calculated from census data and post-census population estimates. During the follow-up, 918 cases of leukaemia in children under 15 years (510 boys, 408 girls) were reported to the RNT (41% of all childhood malignancies), with an overall age-standardised incidence rate of 56 per million person-years. Acute lymphocytic leukaemia (ALL) represented 79% and acute non-lymphocytic leukaemia (ANLL) 16% of the cases, with rates of 43 and 9 per million person-years respectively. There were downward trends in incidence of total leukaemias, ALL and ANLL and 'not otherwise specified' (NOS) combined. Incidence of ALL was highest at 1-4 years of age in boys and girls, whereas ANLL peaked in girls during the first year of life. During 1991-96, the decrease in ALL was significant (P = 0.042). A multivariable Poisson regression model identified significant excesses of ALL for boys, for age groups 1-4 and 5-9 years and for three out of seven regions. Possible reasons for the high rates in Costa Rica are discussed.
UI - 9636655
AU - Kobayashi S; Teramura M; Ito K; Iwabe K; Inaba T; Mizoguchi H
TI - Transcription factor NF-E2 is essential for the polyploidization of a human megakaryoblastic cell line, Meg-J.
SO - Biochem Biophys Res Commun 1998 Jun 9;247(1):65-9
AD - Department of Hematology, Tokyo Women's Medical College, Japan.
Transcription factors regulating the process of megakaryocyte development remain largely unclarified. To clarify them further, we used a human megakaryoblastic cell line, Meg-J, which showed prominant polyploidization and augmented platelet glycoprotein (GP) Ib expression after incubation with thrombopoietin (TPO, c-mpl ligand) and K252a (an indolocarbasole derivative). Under these conditions, we analyzed the expression of the transcription factors and observed that the expression of NF-E2 p45, but not those of GATA-1, GATA-2, Tal-1/SCL, Evi-1, and MafK, was increased after TPO and K252a stimulation. Gel-shift assay confirmed the enhanced binding activity to the NF-E2 site. The abolishment of NF-E2 p45 with NF-E2 antisense oligomers inhibited TPO plus K252a-induced polyploidization. These findings suggest that NF-E2 p45 is essential for the polyploidization of megakaryocytic cells.
UI - 12225999
AU - Rauscher GH; Sandler DP; Poole C; Pankow J; Mitchell B; Bloomfield CD;
TI - Olshan AF Family history of cancer and incidence of acute leukemia in adults.
SO - Am J Epidemiol 2002 Sep 15;156(6):517-26
AD - Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois-Chicago, Chicago, IL 60612, USA. email@example.com
Family history of cancer may represent shared genetic and environmental risk factors for leukemia. The authors examined associations of first-degree family history of cancer with adult acute leukemia incidence by using data on 811 patients (or their proxies) identified at diagnosis and 637 population-based controls in the United States and Canada during 1986-1990. For proxy-interviewed patients, relative risks were elevated for family history of any cancer (relative risk = 1.7, 95% confidence interval (CI): 1.3, 2.4), hematopoietic cancer (relative risk = 1.8, 95% CI: 1.1, 3.0), leukemia (relative risk = 2.4, 95% CI: 1.3, 4.6), and breast cancer (relative risk = 1.7, 95% CI: 1.0, 3.0) but not for colorectal, prostate, or lung cancer. For self-interviewed patients, family history of hematopoietic cancer was inversely associated with leukemia incidence (relative risk = 0.6, 95% CI: 0.4, 1.1). Regardless of patient interview type, history of breast cancer in sisters was positively associated with adult acute leukemia, whereas history of breast cancer in mothers was not. The role of family history of cancer in leukemia etiology is unclear because of differential reporting by patients and proxies. Specifically, self-interviewed patients may underreport cancer in their first-degree relatives. Associations between family history of breast cancer and leukemia incidence may be the result of unmeasured, shared etiologies specific to these cancers.
UI - 11522536
AU - Hernandez JM; Martin G; Gutierrez NC; Cervera J; Ferro MT; Calasanz MJ;
TI - Martinez-Climent JA; Luno E; Tormo M; Rayon C; Diaz-Mediavilla J; Gonzalez M; Gonzalez-San Miguel JD; Perez-Equiza K; Rivas C; Esteve J; Alvarez Mdel C; Odriozola J; Ribera JM; Sanz MA; PETHA Cooperative Group, Spain Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with an ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA.
SO - Haematologica 2001 Aug;86(8):807-13
AD - Servicio de Hematologia, Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain. firstname.lastname@example.org
BACKGROUND AND OBJECTIVES: To analyze in patients with de novo acute promyelocytic leukemia (APL) treated with an ATRA plus anthracyclin-based protocol if the presence of additional cytogenetic aberrations to the t(15;17) influences: 1. clinical and biological presenting features; 2. disease outcome. DESIGN AND METHODS: One hundred and thirteen patients with newly diagnosed APL enrolled in the APL-96 protocol of the Spanish PETHEMA group were studied by conventional karyotyping, FISH and RT-PCR for the PML-RARa fusion. Treatment was homogeneous in all cases and consisted of anthracyclines and ATRA. RESULTS: Additional chromosome aberrations were observed in 30% of cases. The most frequent secondary changes were +8 (14 cases), and abnormalities of chromosomes 9 or 3 (4 patients each), and of chromosomes 1 and 8 (3 cases each). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of APLs with t(15;17) alone and the group of patients with additional changes. Patients with additional changes had a higher rates of complete remission (CR) and 4-year disease-free survival (DFS) (97%, and 97%, respectively) than patients with t(15;17) alone (CR, 70% and DFS, 84%) but these differences were not statistically significant. INTERPRETATION AND CONCLUSIONS: Patients with APL and additional cytogenetic abnormalities do not show different clinical, biological, morphological or molecular features as compared to patients with t(15;17) alone. The prognosis of patients with APL and t(15;17) alone and those with additional changes is similar in both groups. This study indicates that there is no rationale for administering more intensive treatment in APL patients with additional cytogenetic abnormalities receiving ATRA plus anthracycline-based chemotherapy.
UI - 12183408
AU - Taketani T; Taki T; Shibuya N; Kikuchi A; Hanada R; Hayashi Y
TI - Novel NUP98-HOXC11 fusion gene resulted from a chromosomal break within exon 1 of HOXC11 in acute myeloid leukemia with t(11;12)(p15;q13).
SO - Cancer Res 2002 Aug 15;62(16):4571-4
AD - Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
The NUP98 gene has been reported to be fused to 11 partner genes in hematological malignancies with 11p15 translocations. Among NUP98 fusion partner genes, HOXA and HOXD clusters have been reported thus far; however, no HOXC or HOXB clusters have been reported. We identified a novel NUP98-HOXC11 fusion gene in a pediatric patient with de novo acute myeloid leukemia having t(11;12)(p15;q13). The breakpoint of NUP98 was located within a LINE repetitive sequence (HAL1) in intron 12, and the breakpoint of HOXC11 was located within exon 1, resulting in a NUP98-HOXC11 in-frame fusion transcript containing exon 12 of NUP98 fused to a part of exon 1 of HOXC11 with an 8-bp insertion derived from the intron sequence just 5' of the breakpoint of NUP98. The NUP98-HOXC11 fusion protein consists of the NH2-terminal phenylalanine-glycine repeat motif of NUP98 and the COOH-terminal homeodomain of HOXC11. Although the frequency of HOXC11 expression was not high in leukemia cell lines, its expression was significantly more frequent in myeloid than lymphoid leukemia cell lines. These data suggest that the NUP98-HOXC11 fusion protein plays a role in the pathogenesis of myeloid malignancies.
UI - 12183432
AU - Grimwade D; Outram SV; Flora R; Ings SJ; Pizzey AR; Morilla R; Craddock
TI - CF; Linch DC; Solomon E The T-lineage-affiliated CD2 gene lies within an open chromatin environment in acute promyelocytic leukemia cells.
SO - Cancer Res 2002 Aug 15;62(16):4730-5
AD - Division of Medical and Molecular Genetics, Guy's, King's and St. Thomas' School of Medicine, London SE1 9RT, UK. email@example.com
The nature of hemopoietic progenitors subject to leukemic transformation in acute myeloid leukemia (AML) has not been clearly defined. To address this issue, we have used DNase I hypersensitivity assays to study the chromatin structure surrounding the T-lineage-affiliated CD2 gene in the acute promyelocytic subtype of AML (APL). Upstream and downstream flanking regions of CD2 were found to be hypersensitive to DNase I in primary APL blasts, with an identical pattern of hypersensitive sites to those detected in cells of T-lineage. All of the sites were confirmed to be inaccessible to DNase I in B-lineage leukemia cells. The demonstration of T-cell-associated chromatin features in primary APL blasts has implications for the origin of APL that may arise in more primitive progenitors than previously considered to be the case.
UI - 12200691
AU - Takahashi S; Licht JD
TI - The human promyelocytic leukemia zinc finger gene is regulated by the Evi-1 oncoprotein and a novel guanine-rich site binding protein.
SO - Leukemia 2002 Sep;16(9):1755-62
AD - Department of Medicine and Derald H Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York, NY 10029, USA.
PLZF (promyelocytic leukemia zinc finger ) is a transcription factor disrupted in t(11;17)-associated acute promyelocytic leukemia which is highly expressed in undifferentiated myeloid cells. To address the tissue-specific regulation of the promoter, we isolated sequences 1.2-kb 5' to the transcriptional start site. Sequence analysis demonstrated that this region contains one TATA box and several putative transcription factor binding sites including four G/C-rich sites and one Evi-1-like site. A fragment of the promoter spanning 158-bp upstream of the transcription start site displayed relative specificity for PLZF-expressing myeloid cells. Functional promoter assays revealed that an Evi-1-like site at -140/-130 was essential for full promoter activity in every cell line tested while a G-rich site at -15/-7 was important for tissue specificity. Electrophoretic mobility shift assays showed that Evi-1 binds specifically to -140/-130 Evi-1-like site and overexpression of Evi-1 in K562 cells activated the PLZF promoter. UV cross-linking assays showed that the proximal, tissue specific element at -15/-7 bound a novel 28 kDa protein. These results indicate as with other myeloid genes, a relatively small segment of DNA can direct tissue-specific expression, but unlike other myeloid promoters, no critical PU.1 or C/EBP sites were found.
UI - 12172547
AU - Wechsler J; Greene M; McDevitt MA; Anastasi J; Karp JE; Le Beau MM;
TI - Crispino JD Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.
SO - Nat Genet 2002 Sep;32(1):148-52
AD - Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Children with Down syndrome have a 10-20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). While a subset of pediatric AMKLs is associated with the 1;22 translocation and expression of a mutant fusion protein, the genetic alterations that promote Down syndrome-related AMKL (DS-AMKL) have remained elusive. Here we show that leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1, encoding the essential hematopoietic transcription factor GATA1 (GATA binding protein 1 or globin transcription factor 1). Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream. We show that the shorter GATA1 protein, which lacks the N-terminal activation domain, binds DNA and interacts with its essential cofactor Friend of GATA1 (FOG1; encoded by ZFPM1) to the same extent as does full-length GATA1, but has a reduced transactivation potential. Although some reports suggest that the activation domain is dispensable in cell-culture models of hematopoiesis, one study has shown that it is required for normal development in vivo. Together, these findings indicate that loss of wildtype GATA1 constitutes one step in the pathogenesis of AMKL in Down syndrome.
UI - 11885131
AU - Montesinos JJ; Mayani H
TI - [New concepts in the biology of acute myeloid leukemia]
SO - Gac Med Mex 2002 Jan-Feb;138(1):67-76
AD - Unidad de Investigacion en Enfermedades Oncologicas, Centro Medico Nacional Siglo XXI, IMSS. Av. Cuauhtemoc 330, Col. Doctores Mexico, D.F. 06720.
During the last 20 years, several concepts regarding the biology of acute myeloid leukemia (AML) have changed in a profound manner. This has been mainly due to significant advances in the identification, purification and characterization of the primitive hematopoietic cells--including stem and progenitor cells--in which this disorder originates. In the present review article, we discuss some of these new concepts and their relevance in the treatment of AML.
UI - 11933574
AU - Schumacher HR; Alvares CJ; Blough RI; Mazzella F
TI - Acute leukemia.
SO - Clin Lab Med 2002 Mar;22(1):153-92, vii
AD - Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, USA. firstname.lastname@example.org
This article provides a review of the acute leukemias with updated basic and practical information. The main emphasis is on techniques used to arrive at the correct diagnosis. Although morphology and cytochemistry were the mainstays of diagnosis in the past, new developments in immunophenotyping, cytogenetics, molecular biology, and in vitro assays have improved the understanding of this disease dramatically and enable the identification of new entities with distinct clinicobiologic features.
UI - 12139726
AU - Haferlach T; Schoch C; Schnittger S; Kern W; Loffler H; Hiddemann W
TI - Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients.
SO - Br J Haematol 2002 Aug;118(2):426-31
AD - Department of Internal Medicine III, Laboratory for Leukaemia Diagnostics, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany. email@example.com
The French-American-British (FAB) classification and the new World Health Organization (WHO) classification distinguish acute monoblastic leukaemia (AML M5a) from acute monocytic leukaemia (AML M5b). Not much is known about the underlying genetic differences leading to these clearly different phenotypes. We analysed 58 patients with de novo AML M5a and 66 patients with de novo AML M5b in comparison with a whole group of 1603 de novo AML. An aberrant karyotype was found in 75.9% of AML M5a but in only 28.8% of M5b (P < 0.0001) and in 54.7% of all other AML subtypes (P = 0.0015). 11q23/MLL aberrations were detected in 31% of M5a, 12.1% of M5b (P = 0.01) but only 1.3% of all other AML subtypes (P < 0.0001). Trisomy 8 as the sole cytogenetic aberration was found in 22.4% of M5a, but in only 3% of M5b and in 2.5% of all other AML subcategories (P < 0.0001). Although the frequency of the MLL-partial tandem duplication (MLL-PTD) did not differ between the three cohorts (1.7%, 4.5% and 6.1% respectively, NS), the detection of FLT3 length mutations (FLT3-LM) differed significantly. AML M5a showed a low frequency of only 6.9%, but 28.8% of M5b (P = 0.0014) and 23.5% of all other AML revealed a FLT3-LM. In conclusion, we demonstrated genetic, i.e. biological, differences between AML M5a and AML M5b and all other AML. Therefore, AML M5 should further be categorized as two different groups, as proposed by the WHO classification.
UI - 12189545
AU - Eatough JP
TI - Evidence of seasonality in the diagnosis of monocytic leukaemia.
SO - Br J Cancer 2002 Aug 27;87(5):509-10
AD - Medical Physics Department, North Staffordshire Royal Infirmary, Princes Road, Hartshill, Stoke-on-Trent, ST4 7LN, UK. firstname.lastname@example.org
Evidence of seasonality in the diagnosis of monocytic leukaemia in England and Wales is presented, with a maximum diagnosis rate in February/March and a minimum in August/September. Previous published results for monocytic leukaemia are of small sample size yet appear consistent with this finding.
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