Abstract
ABCB1 is a member of the ATP binding cassette transporter family and high ABCB1 activity is considered as a poor prognostic factor in acute myeloid leukemia (AML) treated with intensive chemotherapy, its direct relation with drug resistance remains unclear. We evaluated ABCB1 activity in relation with clinical parameters and treatment response to standard chemotherapy in 321 patients with de novo AML. We assessed multiple clinical relationships of ABCB1 activity—ex vivo drug resistance, gene expression, and the ABCB1 inhibitor quinine were evaluated. ABCB1 activity was observed in 58% of AML and was linked to low white blood cell count, high expression of CD34, absence of FLT3-ITD, and absence of mutant NPM1. Moreover, ABCB1 activity was associated with worse overall- and event-free survival. However, ABCB1 activity did not directly lead to ex vivo drug resistance to anthracyclines. We found that ABCB1 was highly correlated with gene expressions of BAALC, CD34, CD200, and CD7, indicating that ABCB1 expression maybe a passenger characteristic of high-risk AML. Furthermore, ABCB1 was inversely correlated to HOX cluster genes and CD33. Thus, low ABCB1 AML patients benefited specifically from anti-CD33 treatment by gemtuzumab ozogamicin in addition to standard chemotherapy. We showed prognostic importance of ABCB1 gene expression, protein expression, and activity. Furthermore, ABCB1 was not directly linked to drug resistance, ABCB1 inhibition did not improve outcome of high ABCB1 AML patients and thus high ABCB1 may represent a passenger characteristic of high-risk AML.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous disease and chemotherapy resistance is the major cause of leukemia related deaths [1]
We examined clinical outcome in high ABC subfamily B-member 1 (ABCB1) activity AML patients treated with the combination of the ABCB1 inhibitor quinine with standard chemotherapy and we investigated the role of ABCB1 in AML patients treated with gemtuzumab ozogamicin (GO) plus chemotherapy
A positive ABCB1 phenotype was defined as a V/E ratio greater than 1.5 within the blast population and this was detected in 58% of AML (94 of 161)
Summary
Acute myeloid leukemia (AML) is a heterogeneous disease and chemotherapy resistance is the major cause of leukemia related deaths [1]. Regardless of known molecular alterations, unexplained treatment failures still occur due to anti-leukemia drug resistance. ABC subfamily B-member 1 (ABCB1) known as permeability glycoprotein and multi-drug resistance (P-gp or MDR1), has been extensively studied in solid cancers and leukemia [4]. 50% of AML patients have blast cells that express ABCB1 [5] and over-expression of ABCB1 was associated with lower complete remission (CR) rates and higher relapse rates in patients treated with standard chemotherapy based on the combination of an anthracycline with cytarabine [5,6,7,8]. Higher ABCB1 activity and lower CD33 expression was related to lower response rates in AML patients treated with gemtuzumab ozogamicin (GO), an immunoconjugate of an anti-CD33 antibody with a toxic calicheamicin-γ derivative [11]. ABCB1 expression may be useful in clinical routine diagnostics to optimize chemotherapy selection
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