title: Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia.
abstract: Acute Promyelocytic Leukemia (APL) is a distinct subtype of myeloid leukemia that in the USA alone affects more than 3,000 individuals every year. APL is characterized by three distinct and unique features: i) the accumulation in the bone marrow of tumor cells with promyelocytic features; ii) the invariable association with specific translocations which always involve chromosome 17 and the Retinoic Acid Receptor alpha (RAR alpha) locus; iii) the exquisite sensitivity of APL blasts to the differentiating action of Retinoic Acid (RA). These features have led APL to become the paradigm for therapeutic approaches utilizing differentiating agents. The last 5 years have provided crucial insights into the molecular basis of APL. RAR alpha translocates in 99% of cases to a gene located on chromosome 15 that we initially named myl and subsequently has been called PML. In a few cases, RAR alpha variably translocates to chromosome 11 where it fuses to the PLZF gene or to a newly described partner, NuMA. In addition, RAR alpha is also found translocated to chromosome 5 where it fuses to the NPM gene. The cloning of variant translocations in APL and the comparative analysis of their associated products is crucial for the understanding of the molecular etiopathogenesis of the disease. The generation of animal models, i.e., transgenic mice expressing the fusion genes, will be instrumental in determining the precise contribution of these fusion genes to leukemogenesis. In fact, mice harboring a PML/RAR alpha transgene whose expression is specifically targeted to the myeloid-promyelocytic lineage develop acute myeloid leukemia with promyelocytic features. Moreover, the functional analysis of the various fusion proteins, as well as RAR alpha partners, is revealing striking common features beneath a misleading structural heterogeneity which unravels a possible unifying molecular mechanism towards APL leukemogenesis.
authors.affiliation: Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kalantry
authors.forename: L
authors.initials: L
authors.lastname: Delva
authors.forename: M
authors.initials: M
authors.lastname: Gaboli
authors.forename: D
authors.initials: D
authors.lastname: Gandini
authors.forename: M
authors.initials: M
authors.lastname: Giorgio
authors.forename: N
authors.initials: N
authors.lastname: Hawe
authors.forename: L Z
authors.initials: LZ
authors.lastname: He
authors.forename: D
authors.initials: D
authors.lastname: Peruzzi
authors.forename: R
authors.initials: R
authors.lastname: Rivi
authors.forename: C
authors.initials: C
authors.lastname: Tribioli
authors.forename: Z G
authors.initials: ZG
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D015321:Gene Rearrangement; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008967:Molecular Biology