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Oncogenic Kinases of Myeloproliferative Disorders Induce Both Protein Synthesis and G1 Activators

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Oncogenic Kinases of Myeloproliferative Disorders Induce Both Protein Synthesis and G1 Activators Letters to the Editor 1885 between the t(8;21) karyotype and MDR-1 gene expression,5,6 expressing cells and t(8;21) patients,7,9 a protein that acts as a suggesting that this transcription factor fusion gene may promote tumour suppressor gene in other contexts. the expression of MDR-1. We therefore tested this hypothesis directly by expressing the RUNX1-RUNX1T1 fusion as a single abnormality in human haematopoietic cell subsets and per- Acknowledgements formed Affymetrix microarray analysis (as described pre- viously)2,7 to determine whether this fusion had any effect on We thank Amanda Gilkes and Megan Musson (Cardiff University) the transcription of MDR genes. Using this approach, we for their technical assistance in processing microarray samples. generated independent replicate sets of data from control and We are grateful to the MRC for access to patient sample material RUNX1-RUNX1T1-matched CD34 þ cultures as well as matched enrolled in the NCRI clinical trials. This work was supported by sets constituting granulocytic (CD14lo,CD36lo,CD15hi)and Leukaemia Research, UK. hi monocytic (CD14 ) unilineage populations (isolated from day 6 A Tonks1, L Pearn1, KI Mills1, AK Burnett1 and RL Darley1 cultures by immunomagnetic sorting). cRNA was prepared from 1Department of Haematology, School of Medicine, Cardiff each sample and hybridized to Affymetrix human 133A University, Cardiff, UK oligonucleotide arrays, which allowed the simultaneous analysis E-mail: [email protected] of six MDR family gene members. In each of these populations, the expression of MDR genes was not significantly different from References controls (Figure 1a–c). In addition, using our cohort of French– American–British (FAB)-M2 patients, there was little difference in 1 Peterson LF, Zhang DE. The 8;21 translocation in leukemogenesis. MDR gene expression between those individuals with a t(8;21) Oncogene 2004; 23: 4255–4262. and those without this abnormality (Figure 1d). We could 2 Tonks A, Tonks AJ, Pearn L, Pearce L, Hoy T, Couzens S et al. therefore find no evidence that RUNX1-RUNX1T1 expression Expression of AML1-ETO in human myelomonocytic cells selec- directly influences MDR gene expression as a single abnormality tively inhibits granulocytic differentiation and promotes their self- renewal. Leukemia 2004; 18: 1238–1245. or in t(8;21) patients. One alternative explanation for the 3 Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, aforementioned observations in AML patients is that other Harrison G et al. The importance of diagnostic cytogenetics on coexisting abnormalities may be influencing the expression of outcome in AML: analysis of 1612 patients entered into the MRC MDR, as suggested by Schaich et al.6 AML 10 trial. The Medical Research Council Adult and Children’s We next addressed the issue of whether the t(8;21) Leukaemia Working Parties. Blood 1998; 92: 2322–2333. abnormality directly influences the susceptibility to chemother- 4 Lutterbach B, Sun D, Schuetz J, Hiebert SW. The MYND motif is required for repression of basal transcription from the multidrug apeutic agents. We therefore assessed the sensitivity of normal resistance 1 promoter by the t(8;21) fusion protein. Mol Cell Biol human cells (expressing RUNX1-RUNX1T1 as a single abnorm- 1998; 18: 3604–3611. ality) to a number of drugs commonly used to treat AML 5 Pearson L, Leith CP, Duncan MH, Chen IM, McConnell T, Trinkaus (Daunorubicin, Cytarabine, Fludarabine, Idarubicin or Etopo- K et al. Multidrug resistance-1 (MDR1) expression and functional side) in comparison with matched controls. Remarkably, none dye/drug efflux is highly correlated with the t(8;21) chromosomal of these agents differentially affected the growth of RUNX1- translocation in pediatric acute myeloid leukemia. Leukemia 1996; 10: 1274–1282. RUNX1T1-transduced cells (Figure 2a–e). As treatment of AML 6 Schaich M, Harbich-Brutscher E, Pascheberg U, Mohr B, Soucek S, commonly involves multiple drugs, we also determined the Ehninger G et al. Association of specific cytogenetic aberrations with effect of combining two or more of these chemotherapeutic mdr1 gene expression in adult myeloid leukemia and its implication agents (using drug concentrations that resulted in 50% reduction in treatment outcome. Haematologica 2002; 87: 455–464. in cell growth as a single agent). Again, we observed little 7 Tonks A, Pearn L, Musson M, Gilkes A, Mills K, Burnett A et al. difference in the in vitro growth response of RUNX1-RUNX1T1- RUNX1-RUNXIT1 induces over-expression of gamma-catenin in human CD34(+) cells, increasing self renewal and impairing expressing cells compared to controls (Figure 2f). granulocytic differentiation. Blood 2005; 106: 841A. Taken together, these data suggest that expression of RUNX1- 8 Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, RUNX1T1 itself has no effect on the intrinsic susceptibility to Hetherington CJ et al. AML1-ETO expression is directly cytotoxic chemicals. This raises the alternative hypothesis that involved in the development of acute myeloid leukemia in the RUNX1-RUNX1T1 moderates the influence of secondary presence of additional mutations. Proc Natl Acad Sci USA 2001; 98: abnormalities, which are required for RUNX1-RUNX1T1- 10398–10403. 8 9 Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs expressing cells to undergo leukaemic transformation. For S et al. Translocation products in acute myeloid leukemia activate example, it is known that RUNX1-RUNX1T1 specifically the Wnt signaling pathway in hematopoietic cells. Mol Cell Biol upregulates the expression of g-catenin in RUNX1-RUNX1T1- 2004; 24: 2890–2904. Oncogenic kinases of myeloproliferative disorders induce both protein synthesis and G1 activators Leukemia (2006) 20, 1885–1888. doi:10.1038/sj.leu.2404361; they may progress to an acute syndrome. V617F mutation of the published online 10 August 2006 Janus kinase 2 (JAK2) kinase are found in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. BCR- ABL fusion occurs in chronic myeloid leukemia, and a variety of Myeloproliferative disorders (MPDs) are clonal proliferative fusions involving platelet-derived growth factor and fibroblast diseases of the hematopoietic stem cells. After an initial phase, growth factor (FGF) receptors are found in other MPDs.1 Fusion Leukemia Letters to the Editor 1886 Table 1 Selection of discriminant genes classified by Onto-Express GO ID Biological process P-value Gene Symbol Probe set DS GO:0006364 rRNA processing 3.07EÀ11 Nola1 1418305_s_at 2.10 Exosc2 1426630_at 1.96 Rnu3ip2 1451293_at 1.46 Mphosph10 1429080_at 1.42 Ddx56 1423815_at 1.41 Ebna1bp2 1428315_at 1.31 Exosc1 1452012_a_at 1.31 GO:0007046 Ribosome biogenesis 4.82EÀ11 Rpl12 1435655_at 1.73 1110017C15Rik 1448480_at 1.63 Rrs1 1456865_x_at 1.63 Nol5a 1426533_at 1.59 Gtpbp4 1450873_at 1.40 2610012O22Rik 1423823_at 1.30 GO:0006412 Protein biosynthesis 3.60EÀ05 Rpl41 1454639_x_at 1.90 Mrps18b 1451164_a_at 1.82 Rpl3 1438527_at 1.79 Rps9 1426958_at 1.69 Eif3s1 1426394_at 1.53 Nola2 1416605_at 1.51 Itgb4bp 1427578_a_at 1.47 Eef1e1 1449044_at 1.45 Eif3s4 1417718_at 1.38 GO:0006457 Protein folding 6.72EÀ03 Dnajc11 1433880_at 1.38 Cct3 1448178_a_at 1.33 Ero1l 1419030_at 1.32 Hyou1 1423291_s_at 1.31 GO:0006511 Ubiquitin-dependent protein catabolism 1,47EÀ02 Usp39 1437007_x_at 1.51 Siah2 1448171_at 1.30 Usp10 1448230_at 1.29 GO:0000398 Nuclear mRNA splicing, via spliceosome 1,65EÀ02 Mki67ip 1424001_at 1.88 Pprc1 1426381_at 1.86 Sfrs2 1415807_s_at 1.46 GO:0000074 Regulation of cell cycle 1.65EÀ02 Axl 1423586_at 1.65 Ccnd2 1430127_a_at 1.51 Cdc25a 1417132_at 1.43 Abbreviation: DS, discriminating score; rRNA, ribosomal RNA. kinases that result from a translocation are made of a starved for 7 h in RPMI plus 0.5% FCS. RNA integrity was constitutively activated kinase domain and an N-terminal region controlled by microanalysis (Agilent Bioanalyzer, Palo Alto, CA, encoded by a partner gene. The activated kinase triggers USA). Preparation of cRNA, hybridizations, washes, detection sustained proliferation and survival of the hematopoietic and quantification were performed as recommended by the cells, but maturation is not affected. supplier (www.Affymetrix.com). Data were analyzed by the We studied the gene expression profiles of murine Ba/F3 cells robust multichip average (RMA) method in R using Bioconduc- transfected by various oncogenic MPD kinases by using whole- tor and associated package. Before analysis, a filtering process genome Affymetrix 430 2.0 mouse oligonucleotide microarrays removed from the data set the genes with low and poorly (www.Affymetrix.com). Ba/F3 cells were grown in Rosewell measured expression as defined by an expression value inferior Park Memorial Institute (RPMI) medium supplemented with to 100 U in all samples, retaining 17.885 genes/expressed 10% fetal calf serum (FCS) and interleukin-3 (IL-3). Expression of sequence tags (ESTs). For paired samples, RNA was prepared an MPD kinase bypasses the IL-3 dependence of Ba/F3 cells. independently from different cultures of cells. The correlation RNA was extracted by using Trizol (Trizol Reagent, Invitrogen between paired samples ranged between 0.97 and 0.98. Life Technologies, Carlsbad, CA, USA) from frozen pellets of: (i) Gene expression profiles of Ba/F3 cells transfected by fusion Ba/F3 cells; (ii) Ba/F3 transfected with different pCDNA express- or mutated kinases (nine samples: BCR-ABL, two BCR-FGFR1, ion vectors expressing a mutant, kinase-defective FOP-FGFR1 two CEP1-FGFR1, two FOP-FGFR1, two V617F JAK2) were KD
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