Acute promyelocytic leukemia and differentiation therapy: molecular mechanisms of differentiation, retinoic acid resistance and novel treatments
Journal Title: Turkish Journal of Hematology - Year 2009, Vol 26, Issue 2
Abstract
Incorporation of all-trans-retinoic acid (ATRA) into the treatment of acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (AML), revolutionized the therapy of cancer in the last decade and introduced the concept of differentiation therapy. ATRA, a physiological metabolite of vitamin A (retinol), induces complete clinical remissions (CRs) in about 90% of patients with APL. In contrast to the cytotoxic chemotherapeutics, ATRA can selectively induce terminal differentiation of promyelocytic leukemic cells into normal granulocytes without causing bone marrow hypoplasia or exacerbation of the frequently occurring fatal hemorrhagic syndromes in patients with APL. However, remissions induced by ATRA alone are transient and the patients commonly become resistant to the therapy, leading to relapses in most patients and thus limiting the use of ATRA as a single agent. Therefore, ATRA is currently combined with anthracycline-based chemotherapy, and this regimen dramatically improves patient survival compared to chemotherapy alone, curing about 70% of the patients. However, 30% of APL patients still relapse and die in five years. Recently, arsenic trioxide (As2O3) was proven to be highly effective in inducing CRs not only in APL patients relapsed after ATRA treatment and conventional chemotherapy but also in primary APL patients. Despite the well-documented clinical efficacy of ATRA, molecular mechanisms responsible for development of ATRA resistance are not well understood. Based on in vitro and clinical observations, several mechanisms, including induction of accelerated metabolism of ATRA, decreased bioavailability and plasma drug levels, point mutations in the ATRA-binding domain of promyelocytic leukemia (PML)-retinoic acid receptor-alpha (RARα) and other molecular events have been proposed to explain ATRA resistance. In this review, the molecular mechanisms of ATRA-induced myeloid cell differentiation and resistance are discussed, together with novel clinical approaches to overcome ATRA resistance in APL.
Authors and Affiliations
Bülent Özpolat
Keywords
Related Articles
- EP ID EP84461
- DOI -
- Views 90
- Downloads 0
Quilty Effect after Extracorporeal Photopheresis in a Patient with Severe Refractory Cardiac Allograft Rejection
Investigation of MDM2 Oncogene Copy Number Alterations in Cases of Chronic Lymphocytic Leukemia
.
The Elusive Diagnosis of Primary Esophageal Lymphoma
.
Artificial Intelligence Approaches in Hematopoietic Cell Transplantation: A Review of the Current Status and Future Directions
The evidence-based literature on healthcare is currently expanding exponentially. The opportunities provided by the advancement in artificial intelligence (AI) tools such as machine learning are appealing in tackling man...
Rituximab-Related Reversible Hepatocellular Damage
To the Editor, Since its approval in 1997 by the US Food and Drug Administration, use of rituximab (MabThera®, Roche,Switzerland) has become widespread, especially for the treatment of non-Hodgkin lymphoma (NHL) and chr...