ABCG2 Is Overexpressed on Red Blood Cells in Ph-Negative Myeloproliferative Neoplasms and Potentiates Ruxolitinib-Induced Apoptosis

Abstract

Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN patients with high risk scores are treated by hydroxyurea (HU), interferon-α, or ruxolitinib, a tyrosine kinase inhibitor. Polycythemia vera (PV) is an MPN characterized by overproduction of red blood cells (RBCs). ABCG2 is a member of the ATP-binding cassette superfamily transporters known to play a crucial role in multidrug resistance development. Proteome analysis showed higher ABCG2 levels in PV RBCs compared to RBCs from healthy controls and an additional increase of these levels in PV patients treated with HU, suggesting that ABCG2 might play a role in multidrug resistance in MPNs. In this work, we explored the role of ABCG2 in the transport of ruxolitinib and HU using human cell lines, RBCs, and in vitro differentiated erythroid progenitors. Using stopped-flow analysis, we showed that HU is not a substrate for ABCG2. Using transfected K562 cells expressing three different levels of recombinant ABCG2, MPN RBCs, and cultured erythroblasts, we showed that ABCG2 potentiates ruxolitinib-induced cytotoxicity that was blocked by the ABCG2-specific inhibitor KO143 suggesting ruxolitinib intracellular import by ABCG2. In silico modeling analysis identified possible ruxolitinib-binding site locations within the cavities of ABCG2. Our study opens new perspectives in ruxolitinib efficacy research targeting cell types depending on ABCG2 expression and polymorphisms among patients.

Thiol catalyzed formation of NO-ferroheme regulates canonical intravascular NO signaling

“…79,80 Another known heme exporter found in erythrocytes and other cells is ATP-binding cassette super-family G member 2 (ABCG2). This transporter is suspected to export and transfer heme directly to serum albumin, 2,42,81,82 and therefore may act as a functional transporter for NO-ferroheme as well. At any given time there is 1.5 -50 µM heme-albumin found in human circulation.…”

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

“…Multidrug resistance proteins 1 and 2, which are encoded by ABCG2 genes, play an important role in the excretion of tyrosine kinase inhibitors. In addition, ABCG2 recognizes a wide range of positively or negatively modified substances and is resistant to most topoisomerases I or II, such as topotecan or doxorubicin, which is the reason for therapeutic failure [ 175 , 176 , 177 , 178 , 179 ]. ABCG2 polymorphism explains the low accumulation of anticancer agents (doxorubicin, tyrosine kinase inhibitors, adriamycin, platinum compounds, sorafenib and mitoxantrone) in cells and their altered chemotherapeutic response [ 180 ].…”