Two Critical Hits for Promyelocytic Leukemia

Abstract

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations that always involve the RARalpha gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes). Due to the reciprocity of the translocation, X-RARalpha and RARalpha-X fusion proteins coexist in APL blasts. PLZF-RARalpha transgenic mice (TM) develop leukemia that lacks the differentiation block at the promyelocytic stage that characterizes APL. We generated TM expressing RARalpha-PLZF and PLZF-RARalpha in their promyelocytes. RARalpha-PLZF TM do not develop leukemia. However, PLZF-RARalpha/RARalpha-PLZF double TM develop leukemia with classic APL features. We demonstrate that RARalpha-PLZF can interfere with PLZF transcriptional repression and that this is critical for APL pathogenesis, since leukemias in PLZF(-/-)/PLZF-RARalpha mutants and in PLZF-RARalpha/RARalpha-PLZF TM are indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

“…We now define a distinct mechanism of inhibition of C/EBPα transcriptional RARα-PLZF, which is always present in t(11;17) APL, derepresses PLZF target genes involved in cell proliferation. Whereas this may explain deregulated cell proliferation, RARα−PLZF also causes differentiation arrest and modifies the phenotype of the disease induced by PLZF-RARα in transgenic mice (12). Thus, our observations unravel a previously undescribed mechanism through which RARα-PLZF can cause differentiation arrest and favor proliferation, by inhibiting C/EBPα activity.…”

“…Furthermore, the presence of RARα-PLZF could facilitate leukemogenesis by eliminating the need for additional hits such as the deletion of the remaining Plzf allele that could dysregulate the control of cell proliferation and myeloid differentiation. Thus, in PLZF-RARα transgenic mice, loss of wild-type Plzf was sufficient to modify a CML-like disease into APL (12), in lieu of the coexpression of RARα-PLZF. The extensive network of protein-protein interaction entertained by both fusion proteins and the functional contribution of these fusion proteins to cell transformation could explain the fact that the incidence of APL does not increase with age, consistent with one or a limited number of rate-limiting mutation(s) (1,35).…”

“…RARα, i.e., chronic myeloid leukemia (CML) (11), into APL (12). Moreover, the presence of RARα-PLZF increases the proliferation and resistance to RA treatment in double transgenic mice (12).…”

“…Moreover, the presence of RARα-PLZF increases the proliferation and resistance to RA treatment in double transgenic mice (12). At the molecular level, RARα-PLZF binds to DNA via the PLZF binding site and derepresses PLZF target genes such as cyclin A, Hoxb2a and c-Myc (13)(14)(15), thereby causing increased proliferation.…”

Leukemia-Associated Fusion Proteins: Multiple Mechanisms of Action to Drive Cell Transformation

“…5,6 A "two hit" model hypothesizes that the fusion protein has leukemogenic potential, but needs to cooperate with one or more additional genetic mutations to trigger leukemia development. 5,7,8 In Acute Promyelocytic Leukemia (APL), the gene coding for the transcription factor RAR (Retinoic Acid Receptor) is fused to PML, to yield the PML-RAR fusion protein. 9,10 Although the t(15;17) represents a unique cytogenetic abnormality in the majority of APL patients, almost 40% of APL cases result in additional karyotypic anomalies, suggesting that indeed human APL results from combined genetic mutations.…”