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Characterisation of the PML/RAR alpha rearrangement associated with t(15;17) acute promyelocytic leukaemia.
- Source :
-
Current topics in microbiology and immunology [Curr Top Microbiol Immunol] 1997; Vol. 220, pp. 81-112. - Publication Year :
- 1997
-
Abstract
- The vast majority of cases of APL are associated with t(15; 17) leading to the formation of PML-RAR alpha, RAR alpha-PML and aberrant PML fusion products. PML-RAR alpha is invariably transcribed and is believed to mediate leukaemogenesis. PML was initially considered to be a transcription factor. However, characterisation of other RING finger containing proteins shows no direct evidence for DNA binding. The RING, B-box, and coiled-coil domains are more likely to represent sites of protein-protein interaction and may be critical for the stability of the multiprotein nuclear domains of which PML is an integral part. In APL the nuclear bodies become disrupted, presumably as a consequence of the presence of PML-RAR alpha and aberrant PML proteins that might render the structure unstable. PML-RAR alpha is capable of binding RXR and sequestering it into the disrupted nuclear domains. Sequestration of RXR would be expected to limit high affinity binding of VDR, TR and residual RARs to DNA response elements and might account for the block in myeloid differentiation at the promyelocyte stage that characterizes APL. Recently PML has been found to have growth suppressor/anti-oncogenic activity. It is unclear whether this is a property of PML itself or reflects a nonspecific function of the PML-associated nuclear domains. Hence the PML/RAR alpha rearrangement alone may be sufficient to cause APL. Abnormal PML function may prevent its growth-suppressor activity, leading to leukaemic transformation; concomitant disruption of retinoid pathways due to sequestration of RXR and/or an abnormal repertoire and character of response element activation mediated by the fusion protein, causing the block in myeloid differentiation (Fig. 3). Disruption of RAR alpha would be expected to account for the similar leukaemic phenotype associated with the t(5;17) and t(11;17) APL cytogenetic variants. Further characterisation of NPM and PLZF at the structural and functional level will determine whether PML and other proteins disrupted in APL associated translocations play an active or purely permissive role in leukaemogenesis and will help dissect the events leading to transformation from those causing blockade of myeloid differentiation and mediating the response to ATRA.
- Subjects :
- Adult
Antineoplastic Agents therapeutic use
Cell Transformation, Neoplastic genetics
Chromosomes, Human, Pair 15 genetics
Chromosomes, Human, Pair 17 genetics
Humans
Leukemia, Promyelocytic, Acute drug therapy
Leukemia, Promyelocytic, Acute pathology
Middle Aged
Neoplasm Proteins physiology
Oncogene Proteins, Fusion physiology
Polymerase Chain Reaction
Promyelocytic Leukemia Protein
Receptors, Retinoic Acid genetics
Receptors, Retinoic Acid physiology
Retinoic Acid Receptor alpha
Signal Transduction
Transcription Factors genetics
Transcription Factors physiology
Tretinoin therapeutic use
Tumor Suppressor Proteins
Chromosomes, Human, Pair 15 ultrastructure
Chromosomes, Human, Pair 17 ultrastructure
Gene Expression Regulation, Leukemic
Leukemia, Promyelocytic, Acute genetics
Neoplasm Proteins genetics
Nuclear Proteins
Oncogene Proteins, Fusion genetics
Translocation, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0070-217X
- Volume :
- 220
- Database :
- MEDLINE
- Journal :
- Current topics in microbiology and immunology
- Publication Type :
- Academic Journal
- Accession number :
- 9103677
- Full Text :
- https://doi.org/10.1007/978-3-642-60479-9_6