Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration.

PURPOSE: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. EXPERIMENTAL DESIGN: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. RESULTS: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. CONCLUSION: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.

Conclusion: patterns of non-territorial autonomy

This article seeks to generalise about the significance of non-territorial autonomy as a mechanism for the management of ethnic conflict on the basis of a set of case studies covering the Ottoman empire and its successor states, the Habsburg monarchy, the Jewish minorities of Europe, interwar Estonia, contemporary Belgium, and two indigenous peoples, the Sami in Norway and Maori in New Zealand. It begins by assessing the extent to which the spatial distribution of ethnonational communities determined the range of autonomy options available—whether these might be territorial or whether only non-territorial autonomy would be realistic. The article continues with an assessment of the significance of ‘autonomy’ in circumstances where the institutions with which it is associated enjoy a non-territorial rather than a territorial writ. It concludes by suggesting that in almost all cases where autonomy is extended to a minority within a state this is exercised on a territorial basis, and that in many cases of non-territorial autonomy, or national–cultural autonomy, the powers assumed by the ‘autonomous’ institutions are substantially symbolic. It argues that notwithstanding the limited empirical evidence for the existence of non-territorial autonomy, this device should not be written off at a normative level.