MDMX Is Widely Expressed in Adult Pre-Cursor B Cell B Acute Lymphoblastic Leukemia and Is a Potential Therapeutic Target.

MDMX is a human homolog of murine double minute 2 (HDM2), which like HDM2, is a negative regulator of p53. In pediatric precursor B-cell (pre-B) acute lymphoblastic leukemia (ALL), p53 expression is associated with poor prognosis. In this study, we assessed MDMX, HDM2, p53 and p21 levels in bone marrow samples from 55 adult patients with pre-B ALL diagnosis. A 110-core tissue microrray was subject to immunohistochemical analysis; in which 10% or more tumor cells stained were considered positive. Results were compared with Philadelphia chromosome (Ph) status (37 Ph-, 18 Ph+) and clinical data. MDMX was found to be expressed in 39 of 49 cases (80%), whereas HDM2 was expressed in 14 of 54 cases (26%). All 14 cases positive for HDM2 were also positive for MDMX (P < 0.05). Median survival duration was 138 weeks in the Ph- group and 48 weeks in the Ph+ group (P < 0.001). p53 was expressed more often in the Ph+ group than in Ph- group (10 of 17 versus 10 of 36, P < 0.05), as was p21 (11 of 17 versus 6 of 34, P < 0.003). In the Ph+ group, patients with tumor cells positive for p53, HDM2, and MDMX had a worse prognosis than other patients (35 weeks versus 61 weeks, P < 0.002). Western blot analysis of protein extracts of blasts isolated from patients with pre-B ALL confirmed the expression of MDMX or its variants. Furthermore, only 1 of 5 cases demonstrated missense mutation of p53 genes. Thus MDMX was expressed in most of these cases of pre-B ALL, suggesting that MDMX may be a potential therapeutic target. The higher incidence of MDMX expression seemed to be independent of p53. P21 expression by the blasts of a subset of ALL cases indicated that the p53 pathway was functional.