A novel target for leukemia therapy?

NEOPLASIA

Acute promyelocytic leukemia (APL) is a rare example of a hematopoietic malignancy for which identification of the altered pathways of proliferation, differentiation, and apoptosis has led to improved survival in and management of patients with the disease. Alteration of the gene coding for the retinoic acid receptor (RAR) is invariably found in all the different APL subtypes involving chromosome 17 and is responsible for the blockage of myeloid differentiation at the promyelocytic stage. The altered partner in all the different fusion proteins (promyelocytic leukemia [PML], promyelocytic leukemia zinc finger [PLZF], Numa, NPM, etc) is thought and in some cases been shown to impair cell proliferation and/or survival, or tumor suppression control. Extensive deciphering of the normal functions of the RARA in granulocytic differentiation and that of its altered analogs (X-RARA) has clarified the role played by its partners (coactivators and corespressors) in the retinoic acid nuclear complex (RANC) in transcriptional control of RA target genes. This molecular information was collected at the same time as differentiation therapy with all-trans retinoic acid (ATRA) was translated into clinical practice and has allowed us to better understand the structure-dose response (receptor affinity and efficacy of the natural ligands) and the resistance of the PLZF-RARA subtype linked to a strong inhibition of the corepressors. These molecular characterizations lead to a better molecular definition of the disease, targeted therapy, and permit an exact molecular diagnostic and molecular monitoring of minimal residual disease.

Though novel therapeutic approaches (ATRA and/or AS203) have significantly improved event-free survival at 5 years, some patients are still at risk of relapse and cure is not always achieved by targeting differentiation and apoptosis. This suggests that the leukemic stem cell is not successfully removed and that other pathways involved in the leukemogenetic event should be targeted. In this issue of Blood, Zheng and colleagues (page 3535) build on some of their previous studies by elegantly showing how the oncoproteins PML-RARA and PLZF-RARA affect not only differentiation, survival, and tumor suppression, but also the self-renewal of the hematopoietic progenitors. By using purified murine Sca1⁺ Lin^- stem cells transfected with retroviruses expressing the oncoprotein proteins, Zheng et al confirm the roles of these proteins in the inhibition of granulocytic differentiation induced by granulocyte-colony-stimulating factor and the increased advantage of proliferation and survival. The importance of their study is to pin down a novel altered pathway in APL leukemogenesis, the Wnt pathway known to be involved in self-renewal and stem cell proliferation. The authors show that transfected cells as well as fresh leukemic cells express high levels of γ-catenin and that γ-catenin-transfected Sca1⁺ cells have increased self-renewal. Furthermore, the oncoproteins activate the γ-catenin promoter, thus providing a novel coherent explanation for the leukemogenesis of APL. In colorectal cancers, c-myc and cyclin D1 are crucial targets mediating the potent proliferative activities of Wnt cascade mutations. Interestingly, contrary to β-catenin, γ-catenin does not need to be mutated for its transforming activity. Whether this is the only pathway of self-renewal involved in APL and whether it can successfully be targeted for therapeutic use remain to be demonstrated.