Transcription therapy for acute promyelocytic leukaemia.
Transcription factors are proteins that regulate gene transcription and expression. In many cases of acute leukaemia chromosomal aberrations are translocations of transcription factors which change their expression and induce the leukaemic phenotype. These abnormal transcription factors are tumour-specific and can be targets for novel treatments approaches. Acute promyelocytic leukaemia (APL) is a distinct and unique subtype of acute myeloid leukaemia (AML) characterised by a reciprocal translocation between chromosomes 15 and 17 t(15q22;17q21). The breakpoints of chromosome 15 and 17 are in the PML and RARalpha genes, respectively, forming the fusion PML-RARalpha gene expressed exclusively and universally in APL. The normal RARalpha is an all-trans retinoic acid- (ATRA-)dependent transcription factor involved in the normal differentiation of myeloid cells. The aberrant fusion PML-RARalpha protein remains sensitive to ATRA and underlies the pathogenesis of the APL. ATRA modulation of gene transcription mediated by PML-RARalpha 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 in vivo differentiation of the APL cells. Randomised clinical trials have shown 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 increase the complete remission rate compared to chemotherapy alone. In addition, the relapse rate was significantly lower for patients randomised to induction with concurrent ATRA/chemotherapy than with ATRA followed by chemotherapy. Chemotherapy and/or ATRA maintenance may further improve the long-term outcome compared to no maintenance. PML-RARalpha fusion transcripts can be assayed by RT-PCR to identify PCR positive cells during remission, which are highly predictable of a subsequent haematological relapse. The goal of therapy has been modified to induce a molecular remission with a negative PCR to the PML-RARalpha transcript. This is the first example of an effective response to treatment with a ligand binding to a mutated form of its natural transcription factor. The transcription factor mutation, caused by translocation to another gene, underlies the pathogenesis of the disease.
Douer
D
D
Division of Hematology, USC/Norris Cancer Center, 1441 Eastlake Ave. Rm. 3460, Los Angeles, CA 90033, USA. douer_d@mikey.hsc.usc.edu
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015870:Gene Expression; D015321:Gene Rearrangement; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors / Q000494:pharmacology / Q000627:therapeutic use*; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D014212:Tretinoin