The Impact of Molecularly Targeted Therapies Upon the Understanding of Leukemogenesis and the Role of Hematopoietic Stem Cell Transplantation in Acute Promyelocytic Leukemia

Sumimasa      Nagai; Tsuyoshi      Takahashi; Mineo      Kurokawa

Abstract

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia. An abnormal fusion gene, PML/RARA is detected in approximately 98% of patients with APL. PML/RARA confers long-term self-renewal properties to promyelocytes. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are the major molecularly targeted therapies in APL, affect the PML/RARA fusion protein and cause differentiation and apoptosis of APL cells. Although the leukemia-initiating cells of APL may be present in a myeloid progenitor committed compartment, the precise population of those remains to be elucidated. However, recent studies have demonstrated the effect of ATRA and ATO on APL leukemia-initiating cells. Through these studies, we can understand more deeply how current clinical therapies lead to long-lasting remission of APL. ATRA and ATO have improved the prognosis of APL patients and have changed the role of hematopoietic stem cell transplantation (HSCT). At present, HSCT is not indicated for patients with APL in first complete remission, and considered for patients with relapsed APL. In this review, we discuss the three main topics as follows: the leukemia- initiating cells in APL, the current state-of-the-art treatment for newly diagnosed and relapsed APL, and the role of HSCT in APL patients.

Keywords: Acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, leukemia-initiating cells, PML/RARA, targeted therapy, transplantation, Molecularly Targeted Therapies, acute myeloid leukemia, chromosomes, retinoic acid receptor alpha, leukemic cells, targeted therapies, thyroid hormone receptors, apoptosis, growth, senescence, retinoblastoma protein pathways, histone acetylase activity, triggers degradation, ubiquitin/proteasome system, cyclic adenosine monophosphate, cAMP activates protein kinase, dose-dependent effects, LEUKEMIA, murine, leukemia-repopulating cells, triggered growth arrest, transplantability, CONSOLIDATION THERAPY, chemotherapy, white blood cell, cumulative dose, high-risk, autologous, disease, human leukocyte, hematopoietic stem cell, white blood cell count, prophylactic