Molecular pathogenesis of acute promyelocytic leukaemia and APL variants

It has been 12 years since the simultaneous discovery of the unique sensitivity of acute promyelocytic leukaemia (APL) to differentiation therapy with all-trans retinoic acid (ATRA) and the discovery that the retinoic acid receptor alpha (RAR alpha) gene was rearranged in APL. Nearly 98% of cases of APL are associated with t(15;17) chromosomal translocation and fusion of the PML gene to that encoding RAR alpha to yield an abnormal receptor with the capability of de-regulating gene expression in the haematopoietic cell, causing differentiation block and eventually the development of leukaemia. Since this original discovery, four other translocations were described in APL. In each of these the RAR alpha gene is fused to different partner genes, all yielding aberrant nuclear receptors. These fusion proteins share in common the ability to repress rather than activate retinoic acid targets, one so strongly that the result is an ATRA-resistant form of the disease. In addition each of the partner proteins is important for normal cell growth and development. In this chapter we explore the biology of the RAR alpha, the fusion proteins created in APL and the normal forms of the partner proteins. Through continued study of this disease it is hoped that novel treatments, potentially more applicable to other forms of leukaemia, may arise.