LOW AND MAXIMALLY PHOSPHORYLATED LEVELS OF THE RETINOBLASTOMA PROTEINCONFER POOR-PROGNOSIS IN NEWLY-DIAGNOSED ACUTE MYELOGENOUS LEUKEMIA -A PROSPECTIVE-STUDY

A prior retrospective study suggested that the level of retinoblastoma protein (RB) expression was prognostic for survival in acute myelogen ous leukemia (AML). Individuals with no/low RB protein expression were considered to have loss of RB function, and those with maximally phos phorylated (maxphos) RB were also felt to have nonfunctional RE. To co nfirm this, we prospectively investigated whether the level of RB expr ession was prognostic in AML in a larger cohort of patients. RB level was measured by Western blot and immunohistochemical analysis on perip heral blood samples from 210 newly diagnosed AML patients. Patients we re divided into three groups based on the level of RB protein expressi on (i.e., no or low, elevated, and maxphos) or into two groups on the basis of presumed RB function, altered function (AF-RB, low and maxpho s RB), versus normal function (NF-RB, elevated RB). By combined result s of Western blot and immunohistochemical analysis, 20%, 65%, and 15% of patients had low, elevated, and maxphos RB, respectively. Most pati ents with acute promyelocytic leukemia (APL) with a French-American-Br itish classification of M3 were in the low RE group, likely reflecting a lower proliferative rate of promyelocytes. Analysis was performed w ith and without these APL patients. The median survival was significan tly shorter for both patients with low RE expression (48 weeks, P = 0. 05, including APL patients; 34 weeks, corrected P = 0.008, with APL pa tients excluded) and maxphos RB expression (51 weeks, P = 0.007) compa red to those with elevated RB expression (122 weeks including and 98 w eeks excluding APL patients). Differences were greatest among patients with nonfavorable prognosis cytogenetics (median survival, 34 weeks v ersus 85 weeks; corrected P = 0.001 for AF-RB versus NF-RB). Remission duration was also significantly shorter for non-APL patients with AF- RB versus NF-RB (median survival, 36 weeks versus not reached; correct ed P = 0.02). In multivariate analyses, including cytogenetics, perfor mance status, age, antecedent hematological disorder, and RE status, w ith and without APL patients included, no/low and maxphos-RB protein e xpression were independent predictors for poorer survival. This prospe ctive study confirms that the level of expression of RE is a strong pr ognostic factor in AML, with an inferior survival experience being ass ociated with no/low RB and maxphos RB expression. Therefore, therapeut ic decisions based on the level of RB expression may be indicated, and protocols to incorporate this are currently under development.