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The Sensitivity of Human Cells Expressing RUNX1-RUNX1T1 to Chemotherapeutic Agents

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The Sensitivity of Human Cells Expressing RUNX1-RUNX1T1 to Chemotherapeutic Agents Letters to the Editor 1883 The sensitivity of human cells expressing RUNX1-RUNX1T1 to chemotherapeutic agents Leukemia (2006) 20, 1883–1885. doi:10.1038/sj.leu.2404364; AML.1 The translocation involves DNA rearrangement of the published online 17 August 2006 RUNX1 (aka. AML1, core binding factor (CBFa)) gene on chromosome 21 with the RUNX1T1 (aka. ETO) gene on The translocation (8;21)(q22;q22) is observed in approximately chromosome 8. This abnormality leads to the expression of 12–15% of patients with acute myeloid leukaemia (AML), the RUNX1-RUNX1T1 (aka. AML1-ETO) fusion gene, which making it one of the most frequently observed translocations in promotes self-renewal of haematopoietic cells and also inhibits ab10 10 Control Control RUNX1-RUNX1T1 RUNX1-RUNX1T1 1 1 (log scale) (log scale) Normalised gene expression Normalised gene expression Normalised gene expression 0.1 0.1 TAP1 TAP2 TAP1 TAP2 ABCB1 ABCB6 ABCB7 ABCB1 ABCB6 ABCB7 CD34+ progenitor cells Monocytic progenitor cells (Day 3) (Day 6) c 10 d 10 Control Normal donors RUNX1-RUNX1T1 Other M2 t(8;21)-M2 1 1 (log scale) (log scale) Normalised gene expression Normalised gene expression Normalised gene expression Normalised gene expression 0.1 0.1 TAP1 TAP2 TAP1 TAP2 ABCB1 ABCB6 ABCB7 ABCB1 ABCB6 ABCB7 ABCB11 Granulocytic progenitor AML Patients cells (Day 6) Figure 1 For caption see page 1884. Leukemia Letters to the Editor 1884 a Control b Control c Control RUNX1-RUNX1T1 RUNX1-RUNX1T1 RUNX1-RUNX1T1 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 % Viable cells (normalised to control) % Viable 0 cells (normalised to control) % Viable 0 cells (normalised to control) % Viable 0 0 10-1110-10 10-9 10-8 10-7 0 10-9 10-8 10-7 10-6 0 10-8 10-7 10-6 10-5 10-4 Daunorubicin Cytarabine Fludarabine concentration (M) concentration (M) concentration (M) de Control Control f Control RUNX1-RUNX1T1 RUNX1-RUNX1T1 RUNX1-RUNX1T1 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 % Viable cells (normalised to control) % Viable % Viable cells (normalised to control) % Viable % Viable cells (normalised to control) % Viable 0 0 0 0 0 -9 -8 -9 -9 -9 -9 0 10-9 10-8 10-7 10-6 10 10 2×10 4×10 6×10 8×10 Idarubicin Etoposide concentration (M) concentration (M) Control Flu / Cyt Flu / Cyt Ida Dau / Cyt Dau / Cyt Eto Figure 2 Effect of chemotherapeutic drugs on the growth of human progenitor cells expressing RUNX1-RUNX1T1. Human CD34 þ cells transduced with RUNX1-RUNX1T1 were assayed 3 days after retroviral transduction (in comparison with matched cultures expressing GFP alone). The numbers of GFP þ PIÀ cells were scored by a calibrated flow cytometric assay (as described previously)2 after 2 days in culture treated with increasing doses of (a) Daunorubicin, Dau, (b) Cytarabine, Cyt, (c) Fludarabine, flu, (d) Idarubicin, Ida, (e)Etoposide,Etoor(f) combined drug treatment (using concentrations of drug that inhibited growth by 50%). Data indicate mean71 s.d. of a minimum of three independent replicate analyses. their subsequent differentiation.2 Leukaemias expressing this associated with multi-drug resistance (MDR) gene expres- abnormality are generally associated with a good prognosis in sion.4–6 The MDR-1 gene encodes P-glycoprotein, a cell terms of complete remission, relapse risk and overall survival membrane drug efflux pump. It would be envisaged that compared with other subtypes and tend to respond favourably to patients who are considered to have a good prognosis (such as treatment particularly with high-dose cytarabine and an t(8;21)) would not overexpress MDR-1 (as demonstrated by anthracycline.3 It is currently not known why patients expres- Lutterbach et al.4), otherwise it is likely those individuals would sing the t(8;21) have a good prognosis. The chemosensitivity of show chemoresistance and have a more adverse prognoses. patients with AML has previously been suggested to be Surprisingly, previous studies have found positive correlations Figure 1 MDR gene expression in cells with the RUNX1-RUNX1T1 fusion gene. RNA isolation and Affymetrix microarray analysis was performed on AML patients or human CD34 þ cells transduced with RUNX1-RUNX1T1 retrovirus coexpressing green fluorescent protein (GFP) (470% transduced). Cells expressing GFP alone were used as controls. (a) Day 3 human CD34 þ mixed progenitor cells (n ¼ 5), (b) day 6 transduced CD14hi monocytes (n ¼ 4), (c) day 6 transduced granulocytes cells (CD14lo, CD15hi, CD36lo; n ¼ 4) or (d) AML patients classified as FAB-M2 with (n ¼ 9) or without (n ¼ 29) the t(8;21). Data indicate the average normalized gene expression of MDR genes: TAP, ATP-binding cassette, sub-family B (MDR/TAP), transporter; ABCB1, ATP-binding cassette, sub-family B (MDR/TAP). (For figure see page 1883.) Leukemia 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.
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