A Chimeric Gene, FIP1L1-RARα, Is Isolated from t(4;17)-Positive Acute Promyelocytic Leukemia; a Report of Cloning and Functional Analysis.

Acute promyelocytic leukemia (APL) comprises 5 to 10% of acute myelogenous leukemia, the leukemia cells of which is characterized by the differentiation block at the stage of promyelocyte. In APL cells, a reciprocal translocation in chromosome 17 is usually observed, and consequently, a retinoic acid receptor alpha (RARα) gene is rearranged. The rearranged RARα gene is fused to another gene, and as a result, the product of newly composed fusion gene provokes the onset of APL. So far, there are five RARα partner genes reported; PML gene in 15q22, PLZF gene in 11q23, NPM gene in 5q35, NuMA gene in 11q13 Stat5b in 17q21. We recently experienced APL case, in which a chromosomal translocation, t(4;17) was observed. FISH analysis of leukemia cells indicated that RARα gene was translocated. To identify the RARα-partner gene, we performed 5′-rapid amplification of cDNA end (RACE) and identified FIP1L1 gene as RARα-partner gene. It is known that FIP1L1 gene is fused to PGDFRα gene in the hypereosinophilic syndrome. DNA sequence revealed that exon 15 of FIP1L1 gene was fused to exon 3 of RARα gene. In previous reports, five X-RARα have the common character;

1. X-RARα manifests homodimerization.

2. X-RARα suppresses retinoic acid-induced transcription.

We examined that FIP1L1-RARα has these two characters. Transient transfection analysis showed that FIP1L1-RARα has the ability to form homodimer. And luciferase assay suggested that FIP1L1-RARα suppressed the retinoic acid-induced transcriptional activity at the physiological concentration of all-trans retinoic acid (ATRA). And the level of luciferase activity suppressed by FIP1L1-RARα was similar to that suppressed by PML-RARα. And the therapeutic concentration of ATRA activated the significant level of luciferase activity. Thus, in vitro analysis suggested that ATRA treatment could be effective to FIP1L1-RARα-positive APL patients. Consistent with the results of in vitro analysis, ATRA treatment was clinically effective, and the patient achieved complete remission after five weeks of ATRA treatment. Collectively, we suggest that FIP1L1-RAR? is the sixth pathogenic gene of APL.