共查询到20条相似文献,搜索用时 31 毫秒
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Hahn CN Chong CE Carmichael CL Wilkins EJ Brautigan PJ Li XC Babic M Lin M Carmagnac A Lee YK Kok CH Gagliardi L Friend KL Ekert PG Butcher CM Brown AL Lewis ID To LB Timms AE Storek J Moore S Altree M Escher R Bardy PG Suthers GK D'Andrea RJ Horwitz MS Scott HS 《Nature genetics》2011,43(10):1012-1017
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Wechsler J Greene M McDevitt MA Anastasi J Karp JE Le Beau MM Crispino JD 《Nature genetics》2002,32(1):148-152
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Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia,myelodysplastic syndromes and acute myeloid leukemia 总被引:24,自引:0,他引:24
Tartaglia M Niemeyer CM Fragale A Song X Buechner J Jung A Hählen K Hasle H Licht JD Gelb BD 《Nature genetics》2003,34(2):148-150
We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function. 相似文献
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Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). 相似文献
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New studies reveal that 20% of individuals with acute myeloid leukemia harbor somatic mutations in DNMT3A (encoding DNA methyltransferase 3A). Although these leukemias have some gene expression and DNA methylation changes, a direct link between mutant DNMT3A, epigenetic changes and pathogenesis remains to be established. 相似文献
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《Revue Francophone des Laboratoires》2002,2002(344):25-30
Immunophenotyping has become essential to the diagnosis of acute leukemia, lymphoblastic as well as myeloid. The use of CD45 antibody improves the discrimination of cellular populations and the identification of blast cells.Immunophenotyping allows to define several subgroups, some of them being correlated with cytogenetic or molecular abnormalities. It identifies rare forms of AL.A systematic immunophenotyping of acute leukemia is also interesting for the detection of leukemia-associated phenotypes, which are the basis of the minimal residual disease analysis by flow cytometry. 相似文献
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Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia 总被引:1,自引:0,他引:1
Yan XJ Xu J Gu ZH Pan CM Lu G Shen Y Shi JY Zhu YM Tang L Zhang XW Liang WX Mi JQ Song HD Li KQ Chen Z Chen SJ 《Nature genetics》2011,43(4):309-315
Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases. 相似文献
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Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia 总被引:16,自引:0,他引:16
Hu Y Liu Y Pelletier S Buchdunger E Warmuth M Fabbro D Hallek M Van Etten RA Li S 《Nature genetics》2004,36(5):453-461
The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia. 相似文献
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《Revue Francophone des Laboratoires》2002,2002(344):47-54
The cure rate of children with acute lymphoblastic leukemia approaches 80 %. Numerous prognostic factors have been identified, based on clinical, biological and therapeutic data. The treatment can be more intensive for patients with a high risk of relapse. On the other hand, a less aggressive therapy may be administered to patients with good probability of long term survival. Prognostic factors of childhood ALL include : age, white blood cell count, cytogenetics, early response to treatment. The detection of minimal residual disease with new molecular or immunological techniques is useful to adapt the intensity of the treatment. Treatment consists of multiagent chemotherapy, with remission induction, consolidation, prevention of central nervous system relapses. For the majority of children with ALL, this treatment is based on intensive systemic therapy and methotrexate administered intrathecally.Delayed intensification has contributed to improve the outcome of childhood ALL. Continuation therapy is required in ALL, with daily administration of 6-mercaptopurine and weekly administration of methotrexate. With more and more patients who become long term survivors of childhood ALL, it is important to evaluate and to prevent the late sequelae.The outcome of patients with acute myeloid leukemia is not as successful as for patients with ALL. Treatment consists of several courses of an association of anthracyclines and aracytine. Genoidentical bone marrow transplantation in first complete remission is indicated for the majority of the patients ; ATRA has substantially improved the prognosis of patients with acute promyelocytic leukemia.The studies of gene expression profile at diagnosis of acute leukemia could improve the characterization of prognostic factors and could help to find new therapeutic targets. 相似文献
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Graubert TA Shen D Ding L Okeyo-Owuor T Lunn CL Shao J Krysiak K Harris CC Koboldt DC Larson DE McLellan MD Dooling DJ Abbott RM Fulton RS Schmidt H Kalicki-Veizer J O'Laughlin M Grillot M Baty J Heath S Frater JL Nasim T Link DC Tomasson MH Westervelt P DiPersio JF Mardis ER Ley TJ Wilson RK Walter MJ 《Nature genetics》2012,44(1):53-57
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis. 相似文献
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Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation 总被引:7,自引:0,他引:7
Stegmaier K Ross KN Colavito SA O'Malley S Stockwell BR Golub TR 《Nature genetics》2004,36(3):257-263
Chemical genomics involves generating large collections of small molecules and using them to modulate cellular states. Despite recent progress in the systematic synthesis of structurally diverse compounds, their use in screens of cellular circuitry is still an ad hoc process. Here, we outline a general, efficient approach called gene expression-based high-throughput screening (GE-HTS) in which a gene expression signature is used as a surrogate for cellular states, and we describe its application in a particular setting: the identification of compounds that induce the differentiation of acute myeloid leukemia cells. In screening 1,739 compounds, we identified 8 that reliably induced the differentiation signature and, furthermore, yielded functional evidence of bona fide differentiation. The results indicate that GE-HTS may be a powerful, general approach for chemical screening. 相似文献
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Klein C Grudzien M Appaswamy G Germeshausen M Sandrock I Schäffer AA Rathinam C Boztug K Schwinzer B Rezaei N Bohn G Melin M Carlsson G Fadeel B Dahl N Palmblad J Henter JI Zeidler C Grimbacher B Welte K 《Nature genetics》2007,39(1):86-92
Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development. 相似文献
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MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. 总被引:31,自引:0,他引:31
Scott A Armstrong Jane E Staunton Lewis B Silverman Rob Pieters Monique L den Boer Mark D Minden Stephen E Sallan Eric S Lander Todd R Golub Stanley J Korsmeyer 《Nature genetics》2002,30(1):41-47
Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets. 相似文献