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: 4.9). 05/2011; 117(10):2156-62. DOI: 10.1002/cncr.25753
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.
    Annals of Hematology 09/2013; · 2.40 Impact Factor
  • Source
    European Journal of Nanomedicine 12/2013; 5(4):175-178.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nanodiamonds (NDs) are promising candidates in nanomedicine, demonstrating significant potential as gene/drug delivery platforms for cancer therapy. We have synthesized ND vectors capable of chemotherapeutic loading and delivery with applications towards chemoresistant leukemia. The loading of Daunorubicin (DNR) onto NDs was optimized by adjusting reaction parameters such as acidity and concentration. The resulting conjugate, a novel therapeutic payload for NDs, was characterized extensively for size, surface charge, and loading efficiency. A K562 human myelogenous leukemia cell line, with multidrug resistance conferred by incremental DNR exposure, was used to demonstrate the efficacy enhancement resulting from ND-based delivery. While resistant K562 cells were able to overcome treatment from DNR alone, as compared with non-resistant K562 cells, NDs were able to improve DNR delivery into resistant K562 cells. By overcoming efflux mechanisms present in this resistant leukemia line, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains.
    Nanomedicine: nanotechnology, biology, and medicine 08/2013; · 6.93 Impact Factor


Available from
May 16, 2014