Concomitant ABCG2 Overexpression and FLT3-ITD Mutation Identify a Subset of Acute Myeloid Leukemia Patients at High Risk of Relapse

Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphological Researches, AOU Udine, Udine, Italy.
Cancer (Impact Factor: 4.89). 05/2011; 117(10):2156-62. DOI: 10.1002/cncr.25753
Source: PubMed


ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors.
The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy.
ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P = .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P = .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%.
Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined.

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Available from: Mario Tiribelli,
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    • "Chigaev AML and membrane transport cancer resistance protein ( BCRP1 ) , later dubbed as a stem cell marker and a target in cancer stem cell therapy ( Ding et al . , 2010 ) . Moreover , ABCG2 protein overexpression in concurrence with FLT3 - ITD mutation identifies a subgroup of AML patients with significantly worse prognosis ( Tiribelli et al . , 2011 ) . Our analysis of the top most significant discriminating genes from all three clusters revealed an unanticipated phenomenon : these clusters were enriched in genes functionally involved in membrane transport – transporters and channels ( Table 1 ) . Here protein functions are described according to UniprotKB 1 and Gene Ontology 2 dat"
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    Frontiers in Pharmacology 06/2015; DOI:10.3389/fphar.2015.00134 · 3.80 Impact Factor
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    • "The first-generation FLT3 inhibitors, including midostaurin, lestaurtinib, tandutinib, sorafenib and sunitinib, are substrates and/or inhibitors of ABCB1 and ABCG2 [29]–[33]. Of note, in one recent study a significant positive correlation was found between FLT3-ITD and ABCG2 overexpression, and DFS was shortest in patients with AML with both FLT3-ITD and ABCG2 overexpression [34]. These data suggest that co-inhibition of FLT3 and of ABCG2 might be beneficial. "
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    • "Co-ordinate regulation of ABCG2 with ABCB1 (and a member of the ABCC family such as ABCC3) and possibly other transporters or resistance mechanisms, could explain why inhibition of a single transporter may not be an effective therapeutic strategy (Marzac et al., 2011; van den Heuvel-Eibrink et al., 2005). Along this same line, a recent report suggested that ABCG2 can be overexpressed in leukemias with a FLT3 internal tandem duplication, with an association between ABCG2 overexpression and reduced disease-free and overall survival but not with response rate (Tiribelli et al., 2011). This finding suggests an association of ABCG2 with the intrinsic biology of the leukemia rather than with drug efflux mediating resistance per se. "
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