Identification of a Second Acute Promyelocytic Leukemia (APL) Patient with the STAT5b-RARα Fusion Gene among PML-RARα-Negative Eastern Cooperative Oncology Group (ECOG) APL Protocol Registrants.

In addition to the PML-RARα fusion gene, which accounts for >98% of APL cases, a common segment of 5′-truncated RARα has been found to fuse with the following 4 alternative genes: promyelocytic leukemia zinc finger (PLZF-RARα), nucleophosmin (NPM-RARα), nuclear mitotic apparatus protein (NUMA-RARα) and signal transducer and activator of transcription 5b (STAT5b-RARα). While recurrent cases of PLZF-RARα and NPM-RARα have been documented, there are only single case reports of NUMA-RARα and STAT5b-RARα. In two Phase III clinical trials, E2491 and C9710, the ECOG registered 10 and 12 presumptive APL patients, respectively, based on initial clinical and cytological assessment, which were negative for PML-RARα by reverse transcriptase-polymerase chain reaction (RT-PCR) testing. In this study, we tested 20/22 of these PML-RARα-negative protocol patients for the presence of the 4 alternative fusion genes by RT-PCR, using the corresponding normal transcripts for the rearranged genes as RNA transcription controls. All specimens were positive for the control gene, while 1 case each was positive for PLZF-RARα or STAT5b-RARα. The karyotypes for these 2 cases, respectively, were 46, XY, t(11:17)(q23;q21) and 46, XY, t(10;11)(q22:q25), i(17)(q10). None of the X-RARα-negative cases had abnormalities of chromosome 17. Immunophenotypically, the PLZF-RARα case was consistent with APL; the STAT5b-RARα case had all features of APL (negative for CD11a, CD18, CD34, HLA-DR) except for weak CD133 expression. These findings imply that it is the RARα rearrangement that prompts the APL immunophenotype. Sequence analysis of the STAT5b-RARα mRNA disclosed the same break/fusion point of the STAT5b gene as the only previously-reported case of STAT5b-RARα-positive APL (