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The chimeric transcription factor E2a-Pbx1 is expressed as a result of the 1;19 chromosomal translocation in some 5% of cases of pediatric acute lymphoblastic leukemia. We investigated the biological and transcriptional consequences of forced expression of E2a-Pbx1 in the interleukin-3 (IL-3) dependent, bone marrow-derived cell line Ba/F3. We show that forced expression of E2a-Pbx1 induces apoptosis in Ba/F3 cells without apparent effects on cell cycle progression. This pro-apoptotic effect is enhanced on cytokine deprivation. Furthermore, using cDNA representational difference analysis (RDA), we show that these cellular effects are associated with marked induction of the gene NDRG1, which was previously identified as a target of transcriptional repression by N-myc and induction by the tumor suppressor protein p53. We identify a portion of the NDRG1 promoter capable of mediating transcriptional induction by E2a-Pbx1 and show that NDRG1 is also induced on simple IL-3 deprivation of BaF3 cells. Although we show that E2a-Pbx1 induction of NDRG1 is not impaired as a result of targeting p53 using HPV E6, and therefore does not appear to be p53-dependent, our results overall are consistent with the notion that induction of NDRG1 by E2a-Pbx1 may represent part of an apoptotic or cytostatic cellular response to oncogene activation. Leukemia (2001) 15, 362-370.

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Background: Genomic instability is a universal hallmark of all cancers. Many of the most commonly used chemotherapeutic agents target this genomic instability by directly damaging the DNA, which results in tumour cell death. Our previous work has revealed that loss of SASH1 is associated with impaired apoptosis and increased cellular proliferation. A new generation of drugs have been developed that target the DNA repair enzyme PARP to induce DNA damage and cell death. SASH1 (SAM and SH3 domain containing protein 1) has been described as a tumour suppressor and in support of this SASH1 mRNA levels are decreased in lung, breast, thyroid and colorectal cancers. Our data demonstrates that SASH1 functions in the repair of DNA damage and loss of SASH1 protein expression could be used as a companion diagnostic for PARP inhibitors. Method: SASH1 IHC staining of lung cancer was correlated with patient survival. DNA damage repair was assessed following the depleted of SASH1 (siRNA). SASH1 protein levels in cell lines were correlated to PARP inhibitor sensitivity. Result: A lung cancer tissue microarray (TMA) of 225 patients was assessed for SASH1 protein level. Low SASH1 levels were associated with an improved patient prognosis in adenocarcinoma on univariate analysis (p ¼ 0.03). Analysis of DNA repair pathways demonstrated that SASH1 plays a role in homologous recombination (HR). Based on this observation, the impact of SASH1 expression on sensitivity to PARP inhibitors was explored. An inverse correlation between SASH1 levels and sensitivity to Olaparib was identified in lung cancer cell lines Figure 1 (R 2 ¼ 0.882). We subsequently analysed Olaparib sensitivity in a panel of SASH1 depleted lung cancer cells that demonstrated increased Olaparib sensitivity. Conclusion: Our results indicate that SASH1 protein expression is a prognostic factor in lung cancer, high levels being associated with a worse prognosis in adenocarcinoma. Low SASH1 expression

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