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New Insights Into MLL Gene Rearranged Acute Leukemias Using Gene Expression Profiling: Shared Pathways, Lineage Commitment, and Partner Genes

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New Insights Into MLL Gene Rearranged Acute Leukemias Using Gene Expression Profiling: Shared Pathways, Lineage Commitment, and Partner Genes Leukemia (2005) 19, 953–964 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes A Kohlmann1, C Schoch1, M Dugas2, S Schnittger1, W Hiddemann1, W Kern1 and T Haferlach1 1Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilians University, Munich, Germany; and 2Department of Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians University, Munich, Germany Rearrangements of the MLL gene occur in both acute role in two main functional categories, namely signaling lymphoblastic and acute myeloid leukemias (ALL, AML). This molecules that normally localize to the cytoplasm/cell junctions study addressed the global gene expression pattern of these or nuclear factors implicated in regulatory processes of two leukemia subtypes with respect to common deregulated 7 pathways and lineage-associated differences. We analyzed 73 transcription. t(11q23)/MLL leukemias in comparison to 290 other acute With respect to the oncogenic activation of MLL in leukemia leukemias and demonstrate that 11q23 leukemias combined So and Cleary proposed two mechanisms. One subset of fusion are characterized by a common specific gene expression partners already displays the required transcriptional activation signature. Additionally, in unsupervised and supervised data potential required for leukemogenesis. The other subset acts via analysis algorithms, ALL and AML cases with t(11q23) segre- gate according to the lineage they are derived from, that is, their homodimerization or oligodimerization domains and myeloid or lymphoid, respectively. This segregation can be therefore can lead in a dimerization-dependent pathway to 8 explained by a highly differing transcriptional program. deregulated transcription. Through the use of novel biological network analyses, essential Interestingly, distinct MLL fusion partners suggest a possible regulators of early B cell development, PAX5 and EBF, were role in the tropism of the leukemia. Certain partner proteins not shown to be associated with a clear B-lineage commitment in only convert MLL to an oncogenic fusion protein but also direct lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional the lineage susceptibility for transformation. MLL-AF4 expres- program was directly assessed. Interestingly, gene expression sing leukemias are mainly diagnosed as pro B ALL (acute profiling did not reveal a clear distinct pattern associated with lymphoblastic leukemia), whereas, for example, fusion partners one of the analyzed partner genes. Taken together, the AF9, AF6, or AF10 are common in myelomonocytic or identified molecular expression pattern of MLL fusion gene monoblastic AML (acute myeloid leukemia) subtypes.9 samples and biological networks revealed new insights into the Microarrays simultaneously assess the abundance of thou- aberrant transcriptional program in 11q23/MLL leukemias. 10 Leukemia (2005) 19, 953–964. doi:10.1038/sj.leu.2403746 sands of mRNA transcripts. During the past few years powerful Published online 7 April 2005 algorithms have been developed and adapted to mine micro- 11 Keywords: acute leukemia; gene expression; microarray; MLL; array data. More recently also applications to interprete gene t(11q23) expression signatures in terms of pathways and networks have evolved. In this study, from a series of 363 acute leukemia patient samples hybridized to a set of high-density microarrays representing a near complete human genome, analyses were Introduction performed to (i) identify t(11q23)/MLL gene signatures compared to numerous specific subtypes of acute leukemias, (ii) discrimi- The MLL gene (also termed ALL-1, HRX, and TRX1) located at nate t(11q23)/MLL-positive AML from t(11q23)/MLL ALL sam- chromosome band 11q23 is a recurrent target of chromosomal ples, (iii) investigate signatures correlated with MLL-AF9 and translocations in acute leukemias, particularly prevalent in other MLL partner genes, and (iv) decipher common biological infant leukemias and treatment-related secondary leukemias, networks. Specifically we addressed the question how the and associated with dismal prognosis.1–3 Reciprocal transloca- differing MLL partner genes influence the global gene expression tions associated with the MLL gene result in in-frame fusion signature and whether pathways could be identified to explain transcripts with various partner genes from at least 50 distinct the molecular determination of MLL leukemias occurring in gene loci.4 In addition, a partial tandem duplication of the MLL both the myeloid and lymphoid lineages. gene has been reported.5 The class of oncogenic MLL fusion proteins consists of the N-terminal portion of the MLL protein fused to C-terminal portions of a fusion partner. Experimental systems in which MLL Materials and methods fusion proteins were generated to induce leukemia in mice demonstrated that this fusion to a C-terminal partner is necessary Patient samples for immortalization. Two critical regions within MLL were identified: a region with three AT hook DNA-binding motifs and This study included bone marrow samples from 363 adult acute 6 the DNA methyltransferase homology region. The MLL fusion leukemia patients at diagnosis representing distinct precursor partners act via dominant gain of function and seem to play a B-ALL subtypes t(11q23)/MLL, t(8;14), t(9;22) and precursor T-ALL as well as AML subtypes with t(11q23)/MLL, t(8;21), Correspondence: A Kohlmann, Laboratory for Leukemia Diagnostics, t(15;17), inv(16), or complex aberrant karyotype (Supplementary Department of Internal Medicine III, Ludwig-Maximilians University, Table 1). In AML with t(11q23)/MLL, 15 out of 48 cases were Marchioninistr. 15, 81377 Munich, Germany; therapy-related. Seven out of these 15 cases followed exposure Fax: þ 49 89 7095 4971; E-mail: [email protected] to topoisomerase II inhibitors. All samples were sent between Received 25 October 2004; accepted 26 January 2005; Published December 1998 and February 2004 for reference diagnostics to online 7 April 2005 our laboratory and were registered in our leukemia database.12 Gene expression profiling in t(11q23)/MLL acute leukemias A Kohlmann et al 954 Prior to therapy, all patients gave their informed consent for graphically as nodes (genes) and edges (the biological relation- participation in the current evaluation after having been advised ships between the nodes). Nodes are further displayed using about the purpose and investigational nature of the study as well various shapes that represent the functional class of the gene as of potential risks. The study design adhered to the declaration product. Edges are displayed with various labels that describe the of Helsinki and was approved by the ethics committees of the nature of the relationship between the nodes. The length of an participating institutions prior to its initiation. The diagnosis was edge reflects the evidence supporting that node-to-node relation- performed by an individual combination of cytomorphology, ship, in that edges supported by more articles from the literature cytogenetics, fluorescence in situ hybridization (FISH), multi- are shorter. A detailed description of the procedure and various parameter-immunophenotyping, and molecular genetics. In legends are available online in the Supplementary section. particular, a thorough characterization of the t(11q23)/MLL samples was warranted. Cytogenetic characterization, FISH on interphase nuclei and/or metaphases, and MLL fusion transcripts Results PCR detection was performed as previously described.3 Distinct gene expression signatures in t(11q23)/MLL leukemias Gene expression profiling and statistical methods We first compared the expression profiles of all 73 adult Microarray analyses were performed as previously described t(11q23)/MLL-positive samples (n ¼ 25 ALL and n ¼ 48 AML utilizing the GeneChip System (Affymetrix, Santa Clara, CA, with t(11q23)/MLL) to 204 adult myeloid and 86 lymphoblastic USA) and the HG-U133 microarray set.13–16 Details on the leukemia samples with other defined genetic aberrations). In a procedure are provided in the online section. supervised data analysis approach, a robust set of differentially For supervised statistical analyses, samples were accordingly expressed genes was identified which accurately stratified the grouped and for each disease entity differential genes were samples according to their underlying cytogenetic and immuno- calculated by means of t-test-statistic (two-sample t-test, unequal phenotypic characteristics, that is, myeloid subclasses, precursor variances).17 We applied the software package R version 1.7.1 B-lineage, or precursor T-lineage ALL. In detail, for lympho- (http://www.r-project.org/). To address the multiple testing blastic leukemias, t(11q23)/MLL samples (n ¼ 25) were accu- problem, false discovery rates (FDR) of genes were calculated rately separated from precursor B-ALL cases with t(9;22) (n ¼ 42), according to Storey and Tibshirani.18 t(8;14) (n ¼ 12), and precursor T-ALL (n ¼ 32). Figure 1a displays The class prediction was performed using support vector a principal component analysis of 111 ALL samples based on the machines (SVM),19 because there is evidence that SVM-based differential expression of 262 genes. When projected into the prediction slightly outperforms
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