FUSION BETWEEN A NOVEL KRUPPEL-LIKE ZINC FINGER GENE AND THE RETINOIC ACID RECEPTOR-ALPHA LOCUS DUE TO A VARIANT T(11,17) TRANSLOCATION ASSOCIATED WITH ACUTE PROMYELOCYTIC LEUKEMIA

We have identified a unique case of acute promyelocytic leukaemia (APL) with a t(11;17) reciprocal chromosomal translocation involving the retinoic acid receptor alpha (RARalpha) and a previously uncharacterized zinc finger gene. As a result of this translocation, mRNAs containing the coding sequences of the new gene, fused in-frame either upstream of the RARalpha B region or downstream from the unique A1 and A2 regions of the two major RARa isoforms, are expressed from the rearranged alleles. The above gene, which we have termed PLZF (for promyelocytic leukaemia zinc finger), encodes a potential transcription factor containing nine zinc ringer motifs related to the Drosophila gap gene Kruppel and is expressed as at least two isoforms which differ in the sequences encoding the N-terminal region of the protein. Within the haematopoietic system the PLZF mRNAs were detected in the bone marrow, early myeloid cell tines and peripheral blood mononuclear cells, but not in lymphoid cell lines or tissues. In addition, the PLZF mRNA levels were down-regulated in NB-4 and HL-60 promyelocytic cell lines in response to retinoic acid-induced granulocytic differentiation and were very tow in mature granulocytes. Our results demonstrate for the first time the association of a variant chromosomal translocation involving the RARalpha gene with APL, further implicating the RARalpha in leukaemogenesis and also suggesting an important role for PLZF as well as retinoic acid and its receptors in myeloid maturation.