The theory of APL

Abstract

Acute promyelocytic leukemia (APL) is associated with reciprocal and balanced chromosomal translocations always involving the Retinoic Acid Receptor a (RARa) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARa fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and STAT5b genes. As a consequence, X-RARa and RARa-X fusion genes are generated encoding aberrant fusion proteins that can interfere with X and/or RARa function. Here we will review the relevant conclusions and the open questions that stem from a decade of in vivo analysis of APL pathogenesis in the mouse in transgenic and knock-out models. Oncogene (2001) 20, 7216 ± 7222.

Aberrant mRNA translation in cancer pathogenesis: an old concept revisited comes finally of age

“…somatic chromosomal translocations involving the NPM locus (also known as B23/ nucleophosmin) associated with various hemopoietic malignancies; see Redner et al, 1996 and references therein). NPM has been in fact implicated in the control of ribosome biogenesis (Savkur and Olson, 1998 and references therein), processes that may be perturbed by the oncogenic fusion proteins, which result from these chromosomal translocations (see, for instance, Piazza et al, 2001). However, the most compelling example of a 'ribosome disease' is undoubtedly represented by DC, a disease characterized by features of premature aging and increased susceptibility to cancer .…”

Deregulated TGF-β signaling in leukemogenesis

“…Acute promyelocytic leukemia (APL) is associated with reciprocal translocations, which always involve the RARa locus on chromosome 17, which variably translocates and fuses to the PML, PLZF, NPM, NuMA or STAT5B genes (Pandolfi, 2001;Piazza et al, 2001). PML gene is a member of a family of proteins, which share a novel zinc-finger binding motif termed RING and one or two additional Cys/His rich regions (B-Boxes) followed by a predicted coiled-coil domain (Zhong et al, 2000;Salomoni and Pandolfi, 2002).…”

The role of mouse models in translational cancer research: present and future directions

“…A paradigm is represented by the studies on acute promyelocytic leukemia (APL) which has many subtypes, genetically heterogeneous and shows different responses to therapy. 34 At the same time APL is a rare disease, representing approximately 10% of all myeloid leukemias and consequently, given that patients have to be stratified based on the genetic patterns, the number of patients to enroll for clinical trials is frequently never enough to give statistical significance. To overcome these limitations, Pandolfi's group 35 reproduced, in large cohort of mice, various human fusion genes and biological and pathological characteristics of human diseases as well as validate GEMMs for the chemotherapeutic response.…”