Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia

MDM2 overexpression by pediatric ALL cells at initial diagnosis has been linked to poor response to therapy, In the present study, we evaluated the incidence of MDM2 overexpression by ALL cells from pediatric patients at first relapse and compared MDM2 protein levels with in vitro response to adriamycin and with duration of initial complete remission (CR1). Since an important role of MDM2 in enhancing cell proliferation and survival appears to be inhibition of p53 activity, we also evaluated the status of p53 in these patients' leukemic cells, MDM2 protein levels were determined by Western blot analysis of leukemic bone marrow cells obtained from 42 patients with B cell precursor (BCP) ALL who relapsed during or following therapy on standard FOG ALL protocols. Twelve of 42 (29%) cases have MDM2 levels greater than or equal to 10-fold higher than those detected in normal bone marrow mononuclear (NMMC) cells, which express relatively low levels of protein, Thirty cases (71%) expressed MDM2 at levels <10-fold those in NMMC, including 24 MDM2-negative cases (57%). P53 mutations were detected by single-strand conformation polymorphism analysis in two cases. Overexpression of MDM2 (greater than or equal to 10-fold) was significantly correlated with adriamycin resistance and decreased duration of CRI. Eight of 12 (75%) overexpressers showed high levels of in vitro resistance to adriamycin, compared to four of 30 (13%) nonoverexpressers (P < 0.005). The median CR1 for MDM2 overexpressers was 20.5 months (range: 3-75 months) compared to 41 months (range: 8-98 months) for non-overexpressers (P < 0.01). Four of 42 patients failed to achieve CR following reinduction: leukemic cells from three of these patients either overexpressed MDM2 or contained a mutant p53, These results indicate that overexpression of MDM2 plays a significant role in refractory pediatric ALL and is associated with early relapse, adriamycin resistance, and failure to respond to re-induction therapy.