WT1 AS A NEW PROGNOSTIC FACTOR AND A NEW MARKER FOR THE DETECTION OF MINIMAL RESIDUAL DISEASE IN ACUTE-LEUKEMIA

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reve rse transcriptase-polymerase chain reaction (RT-PCR) was used to exami ne relative levels of WT1 gene expression (defined in K562 cells as 1. 00) in 45 patients with acute myelogenous leukemia (AML), 22 with acut e lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AML L), 23 with chronic myelogenous leukemia (CML), and 24 with non-Hodgki n's lymphoma. Significant levels of WT1 gene were expressed in all leu kemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia. the levels of WT 1 gene expression for NHL were significantly lower or even undetectabl e. Clear correlation was observed between the relative levels of WT1 g ene expression (<0.6 v greater than or equal to 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), dise ase-free survival, and overall survival than those with greater than o r equal to 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 ge ne expression. The quantitation of the WT1 gene expression made it pos sible to detect minimal residual disease (MRD) in acute leukemia regar dless of the presence or absence of tumor-specific DNA markers. Contin uous monitoring of the WT1 mRNA was performed for 9 patients with acut e leukemia. In 4 patients, MRD was detected 2 to 8 months before clini cal relapse became apparent. In 2 other patients, the WT1 mRNA gradual ly increased after discontinuation of chemotherapy. No MRD was detecte d in the remaining 3 patients with AWL who received intensive inductio n and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PM L/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detect ed MRD comparable with that obtained from quantitation of WT1 gene exp ression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic l eukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(-4 ) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blo od, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia. (C ) 1994 by The American Society of Hematology.