Transcription therapy for acute promyelocytic leukaemia

Transcription factors are proteins that regulate gene transcription and exp ression. In many cases of acute leukaemia chromosomal aberrations are trans locations of transcription factors which change their expression and induce the leukaemic phenotype. These abnormal transcription factors are tumour-s pecific and can be targets for novel treatments approaches. Acute promyeloc ytic leukaemia (APL) is a distinct and unique subtype of acute myeloid leuk aemia (AML) characterised by a reciprocal translocation between chromosomes 15 and 17 t(15q22;17q21). The breakpoints of chromosome 15 and 17 are in t he PML and RARa genes, respectively, forming the fusion PML-RAR alpha gene expressed exclusively and universally in APL. The normal RAR alpha is an al l-trans retinoic acid- (ATRA-)dependent transcription factor involved in th e normal differentiation of myeloid cells. The aberrant fusion PML-RAR alph a protein remains sensitive to ATRA and underlies the pathogenesis of the A PL. ATRA modulation of gene transcription mediated by PML-RAR alpha results in a major clinical response. Almost all newly diagnosed APL cases can be induced into complete remission with ATRA with or without chemotherapy by i n vivo differentiation of the APL cells. Randomised clinical trials have sh own that the most significant effect of ATRA is an additive or synergistic activity with chemotherapy to improve the long-term outcome of the disease. On the other hand, ATRA with or without induction chemotherapy did not inc rease the complete remission rate compared to chemotherapy alone. In additi on, the relapse rate was significantly lower for patients randomised to ind uction with concurrent ATRA/chemotherapy than with ATRA followed by chemoth erapy. Chemotherapy and/or ATRA maintenance may further improve the long-te rm outcome compared to no maintenance. PML-RAR alpha fusion transcripts can be assayed by RT-PCR to identify PCR positive cells during remission, whic h are highly predictable of a subsequent haematological relapse. The goal o f therapy has been modified to induce a molecular remission with a negative PCR to the PML-RAR alpha transcript. This is the first example of an effec tive response to treatment with a ligand binding to a mutated form of its n atural transcription factor. The transcription factor mutation,caused by tr anslocation to another gene, underlies the pathogenesis of the disease.