Identification of genes with abnormal expression changes in acute myeloid leukemia

Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify previously unrecognized expression changes that occur only in AML blasts. We were particularly interested in those genes with increased expression in AML, believing that these genes may be potential therapeutic targets. To test this hypothesis, we compared gene expression profiles between normal hematopoietic cells from 38 healthy donors and leukemic blasts from 26 AML patients. Normal hematopoietic samples included CD34+ selected cells (N = 18), unselected bone marrows (N = 10), and unselected peripheral bloods (N = 10). Twenty genes displayed AML‐specific expression changes that were not found in the normal hematopoietic cells. Subsequent analyses using microarray data from 285 additional AML patients confirmed expression changes for 13 of the 20 genes. Seven genes (BIK, CCNA1, FUT4, IL3RA, HOMER3, JAG1, WT1) displayed increased expression in AML, while 6 genes (ALDHA1A, PELO, PLXNC1, PRUNE, SERPINB9, TRIB2) displayed decreased expression. Quantitative RT/PCR studies for the 7 over‐expressed genes were performed in an independent set of 9 normal and 21 pediatric AML samples. All 7 over‐expressed genes displayed an increased expression in the AML samples compared to normals. Three of the 7 over‐expressed genes (WT1, CCNA1, and IL3RA) have already been linked to leukemogenesis and/or AML prognosis, while little is known about the role of the other 4 over‐expressed genes in AML. Future studies will determine their potential role in leukemogenesis and their clinical significance. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat. © 2007 Wiley‐Liss, Inc.

[1]  T. Akiyama,et al.  WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. , 1994, Blood.

[2]  G Flandrin,et al.  The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  Natalia Meani,et al.  Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. , 2003, The Journal of clinical investigation.

[4]  G. Ehninger,et al.  Analysis of Flt3-activating Mutations in 979 Patients with Acute Myelogenous Leukemia: Association with Fab Subtypes and Identification of Subgroups with Poor Prognosis , 2022 .

[5]  N. Nara,et al.  Expression of Notchl and Jaggedl Proteins in Acute Myeloid Leukemia Cells , 2001 .

[6]  L. Zhao,et al.  Single-stranded linear amplification protocol results in reproducible and reliable microarray data from nanogram amounts of starting RNA. , 2004, Genomics.

[7]  S. Tomoyasu,et al.  Elevated levels of cyclin A1 and A (A2) mRNA in acute myeloid leukaemia are associated with increased survival , 2003, British journal of haematology.

[8]  N. Hosen,et al.  patients with hematopoietic malignancies product in WT 1 Humoral immune responses against Wilms tumor gene , 2002 .

[9]  P. Pandolfi,et al.  Altered myelopoiesis and the development of acute myeloid leukemia in transgenic mice overexpressing cyclin A1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  F. Kokocinski,et al.  Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype , 2005, Oncogene.

[11]  Erik Andries,et al.  Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. , 2006, Blood.

[12]  S. Langabeer,et al.  Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. , 2002, Blood.

[13]  J. Esteve,et al.  Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. , 2006, Cancer research.

[14]  L. Bergmann,et al.  Down-regulation of wt1 expression in leukemia cell lines as part of apoptotic effect in arsenic treatment using two compounds , 2006, Leukemia & lymphoma.

[15]  C. Flamant,et al.  High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  N. Nara,et al.  Expression of Notch1 and Jagged1 proteins in acute myeloid leukemia cells. , 2001, Leukemia & lymphoma.

[17]  G. Landberg,et al.  Cyclin A1 expression and associations with disease characteristics in childhood acute lymphoblastic leukemia. , 2006, Leukemia research.

[18]  K. Matsumoto,et al.  Expression and transcriptional regulation of the human alpha1, 3-fucosyltransferase 4 (FUT4) gene in myeloid and colon adenocarcinoma cell lines. , 2000, Biochemical and biophysical research communications.

[19]  W. Hiddemann,et al.  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Global approach to the diagnosis of leukemia using gene expression profiling , 2022 .

[20]  J. Aster,et al.  Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. , 2005, Blood.

[21]  H. Koeffler,et al.  Expression of the candidate Wilm's tumor gene, WT1, in human leukemia cells. , 1993, Leukemia.

[22]  T. Asahara,et al.  Glycogen Synthase Kinase 3 and h-prune Regulate Cell Migration by Modulating Focal Adhesions , 2006, Molecular and Cellular Biology.

[23]  W. Watkins,et al.  The genetic regulation of fucosylated and sialylated antigens on developing myeloid cells. , 2001, Advances in experimental medicine and biology.

[24]  J. Radich,et al.  Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia. , 2004, Blood.

[25]  Natalia Meani,et al.  Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. , 2005, Blood.

[26]  J. Olson,et al.  A regression-based method to identify differentially expressed genes in microarray time course studies and its application in an inducible Huntington's disease transgenic model. , 2002, Human molecular genetics.

[27]  T. Walzer,et al.  Plexin C1 Engagement on Mouse Dendritic Cells by Viral Semaphorin A39R Induces Actin Cytoskeleton Rearrangement and Inhibits Integrin-Mediated Adhesion and Chemokine-Induced Migration , 2005, The Journal of Immunology.

[28]  T. Ley,et al.  PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Coccia,et al.  Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. , 2002, Blood.

[30]  Chunaram Choudhary,et al.  Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. , 2003, Blood.

[31]  Y. Sonoda,et al.  Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. , 1997, Blood.

[32]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[33]  N. Ueki,et al.  Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia , 2006, Leukemia.

[34]  Eric S. Lander,et al.  Genomic analysis of metastasis reveals an essential role for RhoC , 2000, Nature.

[35]  T. Golub,et al.  Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9 , 2006, Nature.

[36]  S. Heimfeld,et al.  Enumeration of HPC in mobilized peripheral blood with the Sysmex SE9500 predicts final CD34+ cell yield in the apheresis collection , 2000, Bone Marrow Transplantation.

[37]  U. Maurer,et al.  High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. , 1997, Blood.

[38]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  E. Thiel,et al.  CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. , 2002, Blood.

[40]  D. Hockenbery,et al.  Targeting Bcl-2 Related Proteins in Cancer Therapy , 2003, Cancer biology & therapy.

[41]  马文丽,et al.  GEO（Gene Expression Omnibus）：高通量基因表达数据库 , 2007 .

[42]  A. Aventín,et al.  Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. , 2001, Haematologica.

[43]  G. Saunders,et al.  Expression of the Wilms' tumor gene (WT1) in human leukemias. , 1992, Leukemia.

[44]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[45]  R. Verhaak,et al.  Prognostically useful gene-expression profiles in acute myeloid leukemia. , 2004, The New England journal of medicine.

[46]  J. M. Boyd,et al.  Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. , 1995, Oncogene.

[47]  Martin Dugas,et al.  Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. , 2002 .

[48]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[49]  S. Armstrong,et al.  Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. , 2006, Cancer cell.

[50]  S. Heimfeld,et al.  CD34+ progenitor cell selection: clinical transplantation, tumor cell purging, gene therapy, ex vivo expansion, and cord blood processing. , 1996, Journal of hematotherapy.

[51]  G. Heinze,et al.  Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia , 1997, Leukemia.

[52]  Brunangelo Falini,et al.  Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. , 2007, Blood.

[53]  Michael Heuser,et al.  Gene-expression profiles and their association with drug resistance in adult acute myeloid leukemia. , 2005, Haematologica.

[54]  M. Caligiuri,et al.  Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  J. Cayuela,et al.  Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. , 2005, Blood.

[56]  P. Limtrakul,et al.  Inhibitory effect of curcumin onWT1 gene expression in patient leukemic cells , 2006, Archives of pharmacal research.

[57]  A. Megighian,et al.  Transition of Homer isoforms during skeletal muscle regeneration. , 2006, American journal of physiology. Cell physiology.

[58]  C. Marosi,et al.  Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  R. Tibshirani,et al.  Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. , 2004, The New England journal of medicine.

[60]  J. Radich,et al.  FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. , 2001, Blood.

[61]  A. Yoshida,et al.  Genomic structure of the human cytosolic aldehyde dehydrogenase gene. , 1989, Genomics.

[62]  K. Akashi,et al.  MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. , 2004, Cancer cell.

[63]  Stefan Fröhling,et al.  Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. , 2005, Blood.

[64]  G. Duester.  Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. , 2000, European journal of biochemistry.

[65]  K Wheatley,et al.  The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. , 1998, Blood.

[66]  Jeanne Kowalski,et al.  Microarray and Serial Analysis of Gene Expression Analyses Identify Known and Novel Transcripts Overexpressed in Hematopoietic Stem Cells , 2004, Cancer Research.

[67]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[68]  O. Colvin,et al.  Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Jason E. Stewart,et al.  Minimum information about a microarray experiment (MIAME)—toward standards for microarray data , 2001, Nature Genetics.

[70]  P. Meltzer,et al.  Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. , 2005, Blood.

[71]  P. Limtrakul,et al.  Inhibitory effect of curcumin onMDR1 gene expression in patient leukemic cells , 2006, Archives of pharmacal research.

[72]  A. Cossu,et al.  Overexpression of h-prune in breast cancer is correlated with advanced disease status. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[73]  O. Margalit,et al.  Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells , 2006, Leukemia.

[74]  Bas J. Wouters,et al.  Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. , 2006, Cancer cell.

[75]  S. Clark,et al.  Interleukin-3 and granulocyte-monocyte colony-stimulating factor receptors on human acute myelocytic leukemia cells and relationship to the proliferative response. , 1989, Blood.

[76]  R. Xavier,et al.  Homer-3 regulates activation of serum response element in T cells via its EVH1 domain. , 2004, Blood.

[77]  T. Lister,et al.  Characterization of Cells with a High Aldehyde Dehydrogenase Activity from Cord Blood and Acute Myeloid Leukemia Samples , 2005, Stem cells.

[78]  J. Itskovitz‐Eldor,et al.  CD133-positive hematopoietic stem cell "stemness" genes contain many genes mutated or abnormally expressed in leukemia. , 2005, Stem cells.

[79]  Bob Löwenberg,et al.  Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. , 2005, Blood.

[80]  John T. Dimos,et al.  A Stem Cell Molecular Signature , 2002, Science.

[81]  Robert Tibshirani,et al.  Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes. , 2004, Blood.

[82]  L. P. Zhao,et al.  Statistical modeling of large microarray data sets to identify stimulus-response profiles , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[83]  I. Pastan,et al.  Identification of a Set of Seven Genes for the Monitoring of Minimal Residual Disease in Pediatric Acute Myeloid Leukemia , 2006, Clinical Cancer Research.

[84]  D. Fabbro,et al.  FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model , 2005, Oncogene.

[85]  J. Gutkind,et al.  Plexin B Regulates Rho through the Guanine Nucleotide Exchange Factors Leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF* , 2002, The Journal of Biological Chemistry.

[86]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[87]  T. Naoe,et al.  Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. , 1999, Blood.

[88]  D. Cilloni,et al.  Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients , 2002, Leukemia.

[89]  J. Downing,et al.  Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. , 2003, Blood.

[90]  B. Falini,et al.  Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. , 2005, Blood.

[91]  N. Ahn,et al.  The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[92]  I. Kawase,et al.  AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. , 2006, Blood.

[93]  W. Hiddemann,et al.  Analysis of FLT 3 length mutations in 1003 patients with acute myeloid leukemia : correlation to cytogenetics , FAB subtype , and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease , 2002 .

[94]  S. Wasserman,et al.  The pelota locus encodes a protein required for meiotic cell division: an analysis of G2/M arrest in Drosophila spermatogenesis. , 1995, Development.

[95]  C. Marosi,et al.  Prognostic impact of karyotype and immunologic phenotype in 125 adult patients with de novo AML. , 1992, Cancer genetics and cytogenetics.

[96]  T. Ley,et al.  PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[97]  K. Guan,et al.  Semaphorin 4D activates the MAPK pathway downstream of plexin‐B1 , 2006, The Biochemical journal.

[98]  A. Biondi,et al.  A wide role for NOTCH1 signaling in acute leukemia. , 2005, Cancer letters.