ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

Abstract

ATP-binding-cassette (ABC) transporters are evolutionary extremely well-conserved transmembrane proteins that are highly expressed in hematopoietic stem cells (HSCs). The physiological function in human stem cells is believed to be protection against genetic damage caused by both environmental and naturally occurring xenobiotics. Additionally, ABC transporters have been implicated in the maintenance of quiescence and cell fate decisions of stem cells. These physiological roles suggest a potential role in the pathogenesis and biology of stem cell-derived hematological malignancies such as acute and chronic myeloid leukemia. This paper reviews the (patho)physiological role of ABC transporters in human normal and malignant HSCs and discusses its implications for their utility as therapeutical targets to eradicate leukemic stem cells in these diseases.

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…These ABC transporters may serve as therapeutic targets in leukemic stem cells, 164 however it has been notoriously difficult to effectively target these molecules as they also serve essential functions in other tissue types.…”

Flow cytometry‐based assessment of mitoxantrone efflux from leukemic blasts varies with response to induction chemotherapy in acute myeloid leukemia

“…These candidate LSCs display properties of relative chemotherapy resistance including cell cycle quiescence, over expression of ABC transporters, and intrinsic mitoxantrone and DNR efflux capacity (36,37,58). Thus, LSC likely contribute to failure of induction chemotherapy and relapse after CR is obtained.…”

“…The latter were studied as the persistence of LSC is thought to be a mechanism of chemotherapy refractoriness in AML (36). In this study, expression of both MDR1 and BCRP1 was higher in AML cells from chemotherapy refractory patients than in cells from those who achieved CR when the CD34 þ CD38 À fraction enriched for LSC was studied (37).…”

c-MYC Oncoprotein Dictates Transcriptional Profiles of ATP-Binding Cassette Transporter Genes in Chronic Myelogenous Leukemia CD34+ Hematopoietic Progenitor Cells

“…Likewise, ABCG2 is highly expressed in a wide range of stem cells (reviewed in ref. 42) and in primitive hematopoietic CML CD34 þ progenitors (9). ABCG2 is responsible to establish the side population phenotype of HSCs (43), blocking hematopoietic development, and maintaining the stem cell self-renewal potential.…”