Acute leukemia with promyelocytic features in PML/RARα transgenic mice

Abstract

Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations involving the retinoic acid receptor ␣ (RAR␣) locus on chromosome 17. In the majority of cases, RAR␣ translocates and fuses with the promyelocytic leukemia (PML) gene located on chromosome 15. The resulting fusion genes encode the two structurally unique PML͞RAR␣ and RAR␣͞PML fusion proteins as well as aberrant PML gene products, the respective pathogenetic roles of which have not been elucidated. We have generated transgenic mice in which the PML͞RAR␣ fusion protein is specifically expressed in the myeloid-promyelocytic lineage. During their first year of life, all the PML͞RAR␣ transgenic mice have an abnormal hematopoiesis that can best be described as a myeloproliferative disorder. Between 12 and 14 months of age, 10% of them develop a form of acute leukemia with a differentiation block at the promyelocytic stage that closely mimics human APL even in its response to retinoic acid. Our results are conclusive in vivo evidence that PML͞RAR␣ plays a crucial role in the pathogenesis of APL.

A role for PML and the nuclear body in genomic stability

“…This is supported by the very long latent period which precedes leukemia development in these murine models of APL (He et al, 1997(He et al, , 1999Brown et al, 1997; Grisolano et al, 1997). However, in the pre-leukemic phase, PML-RARa transgenic mice display aberrant hemopoiesis, characterized by an indolent myeloproliferative disorder which results in the progressive accumulation of myeloid cells which are blocked at the promyelocytic stage of hemopoietic di erentiation (He et al, 1997(He et al, , 1999Brown et al, 1997;Grisolano et al, 1997). Thus, other genetic events have to occur to transform this myeloproliferative disorder into fullblown leukemia.…”

“…Although there is compelling evidence demonstrating the leukemogenic role of PML-RARa both in vitro and in vivo, PMLRARa seems to be necessary but not su cient for leukemogenesis in transgenic mice (He et al, 1997(He et al, , 1999Brown et al, 1997;Grisolano et al, 1997). This is supported by the very long latent period which precedes leukemia development in these murine models of APL (He et al, 1997(He et al, , 1999Brown et al, 1997; Grisolano et al, 1997).…”

“…Although there is compelling evidence demonstrating the leukemogenic role of PML-RARa both in vitro and in vivo, PMLRARa seems to be necessary but not su cient for leukemogenesis in transgenic mice (He et al, 1997(He et al, , 1999Brown et al, 1997;Grisolano et al, 1997). This is supported by the very long latent period which precedes leukemia development in these murine models of APL (He et al, 1997(He et al, , 1999Brown et al, 1997; Grisolano et al, 1997). However, in the pre-leukemic phase, PML-RARa transgenic mice display aberrant hemopoiesis, characterized by an indolent myeloproliferative disorder which results in the progressive accumulation of myeloid cells which are blocked at the promyelocytic stage of hemopoietic di erentiation (He et al, 1997(He et al, , 1999Brown et al, 1997;Grisolano et al, 1997).…”

“…The PML-RARa fusion protein is leukemogenic in transgenic mice (He et al, 1997(He et al, , 1998Grisolano et al, 1997;Brown et al, 1997). PML-RARa retains most of the functional domains of its parental proteins and can heterodimerize with PML (He et al, 1999).…”

PML4 induces differentiation by Myc destabilization

“…PML-RARa expression blocks the differentiation of hematopoietic precursor cells and is sufficient to produce leukemia in mice (Grisolano et al, 1997;He et al, 1997). The PML-RARa fusion protein exerts its oncogenic function by interfering with the normal functions of RARa and PML.…”