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.

Estimating quantum chromatic numbers

We develop further the new versions of quantum chromatic numbers of graphs introduced by the first and fourth authors. We prove that the problem of computation of the commuting quantum chromatic number of a graph is solvable by an SDP algorithm and describe an hierarchy of variants of the commuting quantum chromatic number which converge to it. We introduce the tracial rank of a graph, a parameter that gives a lower bound for the commuting quantum chromatic number and parallels the projective rank, and prove that it is multiplicative. We describe the tracial rank, the projective rank and the fractional chromatic numbers in a unified manner that clarifies their connection with the commuting quantum chromatic number, the quantum chromatic number and the classical chromatic number, respectively. Finally, we present a new SDP algorithm that yields a parameter larger than the Lovász number and is yet a lower bound for the tracial rank of the graph. We determine the precise value of the tracial rank of an odd cycle.