生物谷報道：根據(jù)最新一期的《Nature》雜志的報道,，利用SNP微陣列在整個基因組范圍內(nèi)對DNA版本數(shù)異常進行高分辨率分析的方法，被用來識別與兒童最常見的癌癥—急性淋巴細胞性白血病有關(guān)的基因病灶,。

對來自242位患者的白血病母細胞所做的分析顯示,，在40% 的B-先祖細胞急性淋巴細胞性白血病病例中，為B-淋巴細胞發(fā)育的關(guān)鍵調(diào)控因子編碼的基因發(fā)生刪除,、放大,、點突變和結(jié)構(gòu)重排等問題。PAX5是最常見的目標(biāo),。所獲得的數(shù)據(jù)表明,，能夠繞開這些基因病灶所造成障礙的小分子細胞分化誘導(dǎo)因子可以作為研究新的治療方法的一個重點，并且更具有普遍意義的是,，它們展示了人們所熟悉的整個基因組范圍內(nèi)進行分析的方法作為識別癌癥中新的小分子病灶的一種手段所具有的潛力,。

FIGURE 1. EBF1 deletions in B-progenitor ALL.

a, EBF1 exons are indicated by vertical lines. The extent of EBF1 deletion in each case is shown by a horizontal line, with large deletions denoted by arrowed lines. Asterisk indicates case BCR–ABL-SNP#5 examined by FISH as shown in c. b, Copy number 'heat map' showing EBF1 deletion in eight B-progenitor ALL cases. H, hypodiploid; O, other; Ph, BCR–ABL1 positive. c, EBF1 FISH analysis of case BCR–ABL-SNP#5 identifies two distinct blast populations, with either mono-allelic or bi-allelic EBF1 deletion; the EBF1 probe is red and the control probe is green. d, Two distinct blast populations differ in surface expression of CD22 and CD10. e, Correlation of blast CD79A and CD10 expression. f, FISH analysis of cells sorted by CD10 expression.

原文出處：

Nature   Volume 446 Number 7137

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia p758
Charles G. Mullighan, Salil Goorha, Ina Radtke, Christopher B. Miller, Elaine Coustan-Smith, James D. Dalton, Kevin Girtman, Susan Mathew, Jing Ma, Stanley B. Pounds, Xiaoping Su, Ching-Hon Pui, Mary V. Relling, William E. Evans, Sheila A. Shurtleff & James R. Downing

doi:10.1038/nature05690

Abstract | Full Text | PDF (941K) | Supplementary information

See also: Editor's summary | News and Views by Golub

相關(guān)基因：

PAX5

Official Symbol: PAX5 and Name: paired box gene 5 (B-cell lineage specific activator) [Homo sapiens]

Other Aliases: BSAP

Other Designations: paired box 5; paired box gene 5 (B-cell lineage specific activator protein); paired box homeotic gene 5; transcription factor PAX 5

Chromosome: 9; Location: 9p13

MIM: 167414

GeneID: 5079

作者簡介：

James R. Downing, MD

Member, St. Jude Faculty
Scientific Director, St. Jude Children's Research Hospital
Chair, Pathology
Associate Director of Basic Research, Cancer Center
Co-Leader, Hematological Malignancies Program
Director, Molecular Pathology Laboratory

Departments

Pathology

Contact Information

James R. Downing, MD
Scientific Director
Chairman, Department of Pathology
MS342, Room D4047D
St. Jude Children's Research Hospital
332 N. Lauderdale
Memphis, TN  38105-2794  USA

E-mail: [email protected]
Phone: (901) 495-3510
FAX: (901) 495-3749

Education

MD - University of Michigan, Ann Arbor (1981)

Research Interests

Developmental hematopoiesis and the role of AML1 in the formation of hematopoietic stem cells Mechanisms of Leukemogenesis Mouse genetics Clinical applications of expression profiling
Selected Publications

Kager L, Cheok M, Wenjian Y, Zaza G, Cheng Q, Panetta JC, Pui C-H, Downing JR, Relling M, Evans W. Folate Pathway Gene Expression Differs in Subtypes of Acute Lymphoblastic Leukemia and Influences Methotrexate Pharmacodynamics. JCI (in press) 2004.

Ross ME, Mahfouz R, Onciu M, Liu H-C, Zhou X, Song G, Shurtleff SA, Pounds S, Cheng C, Ma J, Ribeiro RC, Rubnitz JE, Girtman K, Williams WK, Raimondi SC, Liang D-C, Shih L-Y, Pui C-H, Downing JR. Gene Expression Profiling of Pediatric Acute Myelogenous Leukemia. Blood 104: 3679-87, 2004.

Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC, Rubnitz JE, Razzouk BI, Howard SC, Hudson MM, Cheng C, Kun LE, Raimondi SC, Behm FG, Downing JR, Relling MV, Evans WE. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St. Jude Children’s Research Hospital. Blood 104: 2690-2696, 2004.

Sun W and Downing JR. Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs, while simultaneously inducing an increase in more mature progenitors. Blood 104: 3565-72, 2004.

Zaza G, Yang W, Kager L, Cheok M, Downing JR, Pui C-H, Relling MV, Evans WE. Acute Lymphoblastic leukemia with TEL-AML1 fusion has significantly lower expression of genes involved in purine metabolism and correspondingly lower de novo purine synthesis. Blood 104: 1435-41, 2004.

Imai C, Ross ME, Reid G, Coustan-Smith E, Schultz KR, Pui CH, Downing JR, Campana D. Expression of the adaptor protein BLINK/SLP-65 in childhood acute lymphoblastic leukemia. Leukemia 18:922-5, 2004.

Pui CH, Relling MV, Sandlund JT, Downing JR, Campana D, Evans WE. Rationale and Design of Total Therapy Study XV for Newly Diagnosed Childhood Acute Lymphoblastic Leukemia. Ann Hematol 83 (suppl 1): S124-126, 2004.

Lorsbach RB, Moore J, Ang SO, Sun W, Lenny N, Downing JR. Role of RUNX1 in adult hematopoiesis: analysis of RUNX1-IRES-GFP knock-in mice reveals differential lineage expression. Blood 103: 2522-9, 2004.

Feldman AL, Minniti C, Santi Mariarita, Downing JR, Raffeld M, Jaffe ES. Histiocytic sarcoma following acute lymphoblastic leukaemia: evidence for a common clonal origin. The Lancet Oncology 5:248-250, 2004.

Pui CH, Sandlund JT, Pei D, Rivera GK, Howard SC, Ribeiro RC, Rubnitz JE, Razzouk BI, Hudson MM, Cheng C, Raimondi SC, Behm FG, Downing JR, Relling MV, Evans WE. Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 290: 2001-7, 2003.

Coustan-Smith E, Ribeiro RC, Rubnitz JE, Razzouk BI, Pui CH, Pounds S, Andreansky M, Behm FG, Raimondi SC, Shurtleff SA, Downing JR, Campana D. Clinical significance of residual disease during treatment in childhood acute myeloid leukemia. British Journal of Haematology 123:243-52, 2003.

Onciu M, Behm FG, Downing JR, Shurtleff SA, Raimondi SC, Ma Z, Morris SW, Kennedy W, Jones SC, Sandlund JT. ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases. Blood 102:2642-4, 2003.

Ross ME, Xiaodong Z, Song G, Shurtleff SA, Girtman K, Williams WK, Liu HC, Mahfouz R, Raimondi SC, Lenny N, Patel A, Downing JR. Classification of Pediatric Acute Lymphoblastic Leukemia by Gene Expression Profiling. Blood 102:2951-9, 2003.

Cheok MH, Yang W, Pui CH, Downing JR, Cheng C, Naeve CW, Relling MV, Evans WE. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nature Genetics 34:85-90, 2003.

Lorsbach R, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17: 637-41, 2003.

Li J, Liu H, Downing JR, Yeoh AE, Wong L. Simple rules underlying gene expression profiles of more than six subtypes of acute lymphoblastic leukemia (ALL) patients. Bioinformatics 19:71-78, 2003.

Tonks A, Pearn L, Tonks AJ, Pearce L, Hoy T, Phillips S, Fisher J, Downing JR, Burnett AK, Darley RL. AML 1-ETO promotes extensive self-renewal of human primary erythroid cells. Blood 101: 624-32, 2003.

Hill DA, Riedley SE, Patel AR, Shurtleff SA, Hyer J, Cain AM, Billups CA, Downing JR, Pappo AS. Real-time Polymerase Chain Reaction as an Aid for the Detection of SYT-SSX1 and SYT-SSX2 Transcripts in Fresh and Archival Pediatric Synovial Sarcoma Specimens: Report of 25 Cases from St. Jude Children’s Research Hospital. Pediatr Dev Pathol 6: 24-34, 2003.

Rubnitz JE, Raimondi SC, Halbert AR, Tong X, Srivastava KD, Razzouk BI, Pui CH, Downing JR, Ribeiro RC, Behm FG. Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: a single institution’s experience. Leukemia 16: 2072-7, 2002.

Kogan SC, Anver JB, Brayton C, Cardiff RD, Carter J, Coronado SD, Downing JR, Fredickson T, Haines DC, Harris A, Harris NL, Hiai H, Jaffe ES, MacLennan I, Mufson RA, Pandolfi PP, Pattengale P, Perkins AS, Simpson RM, Tuttle M, Ward JM, Wong J, Morse III HC. Bethesda proposals for the classification of nonlymphoid hematopoietic neoplasms in mice. Blood 100: 238-45, 2002.

Downing JR, Shannon KM. Acute leukemia: A pediatric perspective. Cancer Cell 2:437-445, 2002.

Yeoh E, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Jinyan L, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1:133-143, 2002.

Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui C-H, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT. Gene Expression Signatures Define Novel Oncogenic Pathways is T-Cell Acute Lymphoblastic Leukemia. Cancer Cell 1:75-87, 2002.

Higuchi H, O’Brien D, Downing JR. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1:63-74, 2002.

Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny, N, Downing JR, Meyers S, Hiebert SW. ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol Cell Biology 21: 6470-83, 2001.

Dang J, Inukai T, Kurosawa H, Goi K, Inaba T, Lenny NT, Downing JR, Stifani S, Look AT. The E2A-HLF oncoprotein activates Groucho-related genes and suppresses Runx 1. Mol Cell Biology 21:5935-45, 2001.

Harada Y, Harada H, Downing JR, Kimura A. A hematopoietic-specific transmembrane protein, Art-1, is possibly regulated by AML1. Biochem Biophy Res Comm 284:714-722, 2001.

Downing JR. AML1/CBFâ transcription complex; its role in normal hematopoiesis and leukemia. Leukemia 15: 664-665, 2001.

Mathew S, Rao PH, Dalton J, Downing JR, Raimondi SC. Multicolor spectral karyotyping identifies novel translocations in childhood acute lymphoblastic leukemia. Leukemia 15: 664-665, 2001.

Shih L-Y, Fu J-F, Shurtleff SA, Morris SW, Downing JR. Lack of BCL10 mutations in multiple myeloma and plasma cell leukemia. Genes Chrom Cancer 30:402-406, 2001.

Athale UH, Shurtleff S, Jenkins JJ, Poquette CA, Tan M, Downing JR, Pappo AS. Use of rhabdomyosarcoma, Ewing’s sarcoma family of tumors, and desmoplastic small round cell tumor. J Pediatr Hematol Oncol 23:99-104, 2001.

Bonilla M, Moreno N, Marina N, de Reyes G, Shurtleff SA, Downing JR, Behm FG, Harrison PL, Ribeiro RC, Pena O, Crist WM, Antillon FG. Acute lymphoblastic leukemia in a developing country: preliminary results of a nonrandomized clinical trial in El Salvador. J Pediatr Hematol Oncol 22:495-501, 2000.

Downing JR, Higuchi M, Lenny N, Yeoh AE. Alterations of the AML1 transcription factor in human leukemia. Semin Cell Dev Biol 11:347-360, 2000.

Cai Z, de Bruijn M, Ma X, Dortland B, Luteijn T, Downing JR, Dzierzak E. Haploinsuffiency of AML1 affects the temporarl and spatial generation of hematopoietic stem cells in the mouse embryo. Immunity 12:423-431, 2000.

Strom DK, Nip J, Westendorf JJ, Linggi B, Lutterbach B, Downing JR, Lenny N, Hiebert SW. Expression of the AML1 oncogene shortens the G1 phase of the cell cycle. J Biol Chem 275:3438-3445, 2000.

Okuda T, Takeda K, Fujita Y, Nishimura M, Yagyu S, Yoshida M, Akira S, Downing JR, Abe T. Biological characteristics of the leukemia-associated transcriptional factor AML1 disclose hematopoietic rescue of AML-deficient embryonic stem cells by using a knock-in strategy. Mol Cell Biol 20: 319-328, 2000.

Rubnitz JE, Downing JR, Pui CH. Significance of the TEL-AML fusion gene in childhood AML. Leukemia 13:1470-1471, 1999

Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286(5439):531-537, 1999.

Harada H, Harada Y, O'Brien DP, Rice DS, Naeve CW, Downing JR. HERF1, a novel hematopoietic-specific RING-finger protein, is required for terminal differentiation of erythroid cells. Mol Cell Biol 19(5):3808-3815, 1999.

Scurto P, Rocha MH, Kane JR, Williams WK, Haney DM, Conn WP, Shurtleff SA, Downing JR. A multiplex RT-PCR assay for the detection of chimeric transcripts encoded by the risk-stratifying translocations of pediatric acute lymphoblastic leukemia. Leukemia 12(12):1994-2005, 1998.

Okuda T, Cai Z, Yang S, Lenny N, Lyu C-J, van Deursen J, Harada H, Downing JR. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 91(9):3134-3143, 1998.

Rubnitz JE, Downing JR, Pui C-H, Shurtleff SA, Raimondi SC, Evans WE, Head DR, Crist WM, Rivera GK, Hancock ML, Boyett JM, Buijs A, Grosveld G, Behm FG. TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance. J Clin Onc 15(3):1150-1157, 1997.

Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal murine fetal liver hematopoiesis. Cell 84:321-330, 1996.

Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, Head DR, Pui C-H, Grosveld G, Downing JR. TEL/AML1 fusion occurs in 28% of pediatric B-progenitor cell acute lymphoblastic leukemia and defines a subgroup of patients with a favorable prognosis. Leukemia 9:1985-1989, 1995.