The molecular biology of acute promyelocytic leukemia.
The preceding two years have witnessed an explosion in the accumulation of knowledge relating to the molecular pathogenesis of APL. Critical advances include: The molecular delineation of atypical APL cases with alternative RAR alpha fusion partners, and the demonstration that cells from 2 of the 3 types of 'atypical' APL retain sensitivity to ATRA. Perhaps the key question is why such cases are so rare. However, at a minimum, the presence of such cases argues persuasively that disruption of the retinoid signaling pathway is a (perhaps the) key pathogenetic feature of APL. Although certainly not 'passive' partners, it is likely that PML, PLZF, NPM, and NuMA serve similar functions in the pathogenesis of APL. The demonstration, in transgenic mice, that PML-RAR alpha (and PLZF-RAR alpha) can disrupt normal hematopoiesis and, given sufficient time, cause an APL-like syndrome. the variation in phenotype of the mice, which appears to be a consequence of the specific expression vector used, emphasizes the cell-type-specific nature of PML-RAR alpha function. Continuing functional analysis of PML, PLZF, and RAR alpha. In particular, the demonstration that PML and PLZF can form heterodimers provides a critical functional link between these proteins and offers a tantalizing glimpse at how both, when linked with RAR alpha, can cause APL. The demonstration that PML-RAR alpha is degraded, perhaps via a ubiquitin-dependent pathway, in response to ATRA. This result offers a unifying, if not yet proven, hypothesis to explain the sensitivity of leukemic promyelocytes to ATRA. Unfortunately, it is not known if ATRA can also cause degradation of NPM-RAR alpha or NuMA-RAR alpha (atypical cytogenetic APL variants that retain ATRA responsiveness). Whether PML-RAR alpha degradation is a cause, or consequence, of promyelocytic maturation remains unclear. Continuing insight into retinoid resistance, including the first demonstration of mutations in the PML-RAR alpha molecule from ATRA-resistant patients. The definitive demonstration that the two major PML-RAR alpha isoforms, while having subtle differences in biological activity and producing slightly different APL phenotypes, nevertheless do not, in and of themselves, have prognostic significance in patients treated with ATRA/chemotherapy combinations. Further functional analysis of PML-RAR alpha in vitro. The fascinating finding that PML-RAR alpha is cytotoxic to most cell types suggests that it must function as an oncogene in a very specialized milieu. In addition, the demonstration that both the DBD (from RAR alpha) and dimerization interface (from PML) are required for full in vitro functional activity, coupled with the finding that PML itself is a strong transcriptional suppressor, suggests that PML-RAR alpha may directly repress transcription of RA target genes. The challenge in APL research now is to integrate the above findings into a cohesive, unifying model that explains the biology of APL at a molecular level. The creation and validation of such a model will clarity whether APL is a fortunate medical curiosity or whether it will serve as a paradigm for the development of effective differentiation therapies in other types of human cancers.
Slack
J L
JL
Department of Medicine Roswell, Park Cancer Institute, Buffalo, New York 14263, USA.
Gallagher
R E
RE
D000818:Animals; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000737:chemistry / Q000502:physiology; D011379:Prognosis; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology; D014158:Transcription, Genetic; D014212:Tretinoin / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D014212:Tretinoin; D004247:DNA