根据最新一期的《Nature》杂志的报道，利用SNP微阵列在整个基因组范围内对DNA版本数异常进行高分辨率分析的方法，被用来识别与儿童最常见的癌症—急性淋巴细胞性白血病有关的基因病灶。

对来自242位患者的白血病母细胞所做的分析显示，在40%的B-先祖细胞急性淋巴细胞性白血病病例中，为B-淋巴细胞发育的关键调控因子编码的基因发生删除、放大、点突变和结构重排等问题。PAX5是最常见的目标。所获得的数据表明，能够绕开这些基因病灶所造成障碍的小分子细胞分化诱导因子可以作为研究新的治疗方法的一个重点，并且更具有普遍意义的是，它们展示了人们所熟悉的整个基因组范围内进行分析的方法作为识别癌症中新的小分子病灶的一种手段所具有的潜力。

FIGURE 1. EBF1deletions in B-progenitor ALL.

a,EBF1exons are indicated by vertical lines. The extent ofEBF1deletion 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 inc.b, Copy number 'heat map' showingEBF1deletion in eight B-progenitor ALL cases. H, hypodiploid; O, other; Ph,BCR–ABL1positive.c,EBF1FISH analysis of case BCR–ABL-SNP#5 identifies two distinct blast populations, with either mono-allelic or bi-allelicEBF1deletion; theEBF1probe 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.

原文出处：

Nature  Volume 446 Number 7137

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemiap758

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

相关基因：

PAX5

Official Symbol:PAX5and 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

作者简介：

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:james.downing@stjude.org
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.Blood104: 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.Blood104: 2690-2696, 2004.

Sun W andDowning JR. Haploinsufficiency ofAML1results in a decrease in the number of LTR-HSCs, while simultaneously inducing an increase in more mature progenitors.Blood104: 3565-72, 2004.

Zaza G, Yang W, Kager L, Cheok M,Downing JR, Pui C-H, Relling MV, Evans WE. Acute Lymphoblastic leukemia withTEL-AML1fusion has significantly lower expression of genes involved in purine metabolism and correspondingly lower de novo purine synthesis.Blood104: 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.Leukemia18:922-5, 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 Hematol83 (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.Blood103: 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 Oncology5:248-250, 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.JAMA290: 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 Haematology123:243-52, 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.Blood102:2642-4, 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.Blood102:2951-9, 2003.

Cheok MH, Yang W, Pui CH, Downing JR, Cheng C, Naeve CW, Relling MV, Evans WE. Treatment-specific changes in gene expression discriminatein vivodrug 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).Leukemia17: 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.Bioinformatics19:71-78, 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.Blood101: 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 Pathol6: 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.Leukemia16: 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.Blood100: 238-45, 2002.

Downing JR, Shannon KM. Acute leukemia: A pediatric perspective.Cancer Cell2:437-445, 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 Cell1:133-143, 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 Cell1:75-87, 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 Cell1:63-74, 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 Biology21: 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 Biology21:5935-45, 2001.

Harada Y, Harada H,Downing JR, Kimura A. A hematopoietic-specific transmembrane protein, Art-1, is possibly regulated by AML1.Biochem Biophy Res Comm284:714-722, 2001.

Downing JR. AML1/CBFâ transcription complex; its role in normal hematopoiesis and leukemia.Leukemia15: 664-665, 2001.

Mathew S, Rao PH, Dalton J,Downing JR, Raimondi SC. Multicolor spectral karyotyping identifies novel translocations in childhood acute lymphoblastic leukemia.Leukemia15: 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 Cancer30:402-406, 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 Oncol23:99-104, 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 Oncol22:495-501, 2000.

Downing JR, Higuchi M, Lenny N, Yeoh AE. Alterations of the AML1 transcription factor in human leukemia.Semin Cell Dev Biol11:347-360, 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.Immunity12:423-431, 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 Chem275:3438-3445, 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 Biol20: 319-328, 2000.

Rubnitz JE,Downing JR, Pui CH. Significance of the TEL-AML fusion gene in childhood AML.Leukemia13:1470-1471, 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.Science286(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 Biol19(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.Leukemia12(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.Blood91(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 Onc15(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.Cell84:321-330, 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.Leukemia9:1985-1989, 1995.

                                        摘自《生物谷》