Abstract 1188: Cell-of-origin determines genetic selection and defines T-cell acute lymphocytic leukemia sub-types in mouse models

Abstract

Abstract The cell-of-origin has yet to be identified for most forms of cancer. However, such knowledge would provide insight into the earliest events that initially distinguish a tumor cell from its normal cell-of-origin. Understanding and identifying these events are critical, as these early genetic changes may create targets that can be exploited therapeutically. Unfortunately, the tools to address this question have only recently become available. We have recently completed a forward genetic screen to examine how altering the cell-of-origin affects genetic selection in cancer. To accomplish this we made use of a Cre-inducible Sleeping Beauty (SB) system to initiate transposon mutagenesis in hematopoietic stem cells (HSCs), thymic progenitor cells (TP) or late stage CD4+/CD8+ thymocytes (DP). Each of these approaches produced predominantly T-cell lymphomas with different characteristics. Analysis of transposon-induced mutations in each of the three lymphoma models revealed clear differences in their genetic profiles. For instance, the HSC model was defined by frequent mutations in Notch1 (∼58%). By contrast, lymphomas in the DP model did not have Notch1 mutations, but instead had frequent mutations in Myc, Gfi1, Whsc1 and Akt2. Interestingly, tumors that were initiated in thymic progenitor cells had a genetic profile similar to that seen in the HSC or the DP model. Recently, a sub-type of T-cell acute lymphoblastic leukemia (T-ALL), called early thymic progenitor ALL (ETP-ALL) was described in which the tumor cells resembled ETPs in both surface marker and mRNA expression. In addition, ETP-ALL patients have a much worse prognosis than typical T-ALL patients. We compared gene expression signatures from a subset of HSC and DP lymphomas to that of ETP-ALL and typical T-ALL. Interestingly, tumors from the DP model have a similar gene expression to human ETP-ALL, while HSC tumors show a greater resemblence to typical T-ALL. Our data indicate that ETP-ALL may not arise from an early thymic progenitor, but from a differentiated T-cell that has undergone anaplastic transformation. The implications of this study are that cell-of-origin cannot be inferred from analysis of protein or gene expression patterns in tumors. Our findings also suggest that differentiation state of the cell-of-origin plays a critical role in determining what types of mutations will be selected during transformation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1188.