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 li nked to poor response to therapy, In the present study, we evaluated the in cidence of MDM2 overexpression by ALL cells from pediatric patients at firs t relapse and compared MDM2 protein levels with in vitro response to adriam ycin and with duration of initial complete remission (CR1). Since an import ant 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 p atients' leukemic cells, MDM2 protein levels were determined by Western blo t analysis of leukemic bone marrow cells obtained from 42 patients with B c ell precursor (BCP) ALL who relapsed during or following therapy on standar d 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 monon uclear (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 con formation polymorphism analysis in two cases. Overexpression of MDM2 (great er than or equal to 10-fold) was significantly correlated with adriamycin r esistance and decreased duration of CRI. Eight of 12 (75%) overexpressers s howed high levels of in vitro resistance to adriamycin, compared to four of 30 (13%) nonoverexpressers (P < 0.005). The median CR1 for MDM2 overexpres sers was 20.5 months (range: 3-75 months) compared to 41 months (range: 8-9 8 months) for non-overexpressers (P < 0.01). Four of 42 patients failed to achieve CR following reinduction: leukemic cells from three of these patien ts either overexpressed MDM2 or contained a mutant p53, These results indic ate that overexpression of MDM2 plays a significant role in refractory pedi atric ALL and is associated with early relapse, adriamycin resistance, and failure to respond to re-induction therapy.