Atp-Binding Casette Transporter Expression in Acute Myeloid Leukemia: Association with
            <i>in Vitro</i>
            Cytotoxicity and Prognostic Markers

Varatharajan, Savitha; Abraham, Ajay; Karathedath, Sreeja; Ganesan, Sukanya; Lakshmi, Kavitha M; Arthur, Nancy Beryl Janet; Srivastava, Vivi M.; George, Biju; Srivastava, Alok; Balasubramanian, Poonkuzhali

doi:10.2217/pgs-2016-0150

Cited by 24 publications

(17 citation statements)

References 41 publications

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“…The patients with unfavorable cytogenetics, FLT3-ITD and c-KIT mutations generally expressed statistically higher ABC transporters levels than did the other risk groups. In contrast Varatharajan et al (15) had proposed that the expression of ABCB1 and ABCG2 was significantly lower in FLT3-ITD mutated AML patients compared with FLT3-ITD negative patients. In their study, the authors reported that the expression of ABCB1 and ABCG2 was markedly higher in NPM1-mutated patients than in unmutated patients, yet our study did not find any statistical differences between the expression levels of ABC transporters in NPM1-mutated and unmutated cases, except regarding ABCC4.…”

Section: Discussionmentioning

confidence: 84%

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Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia

Liu

Gong

et al. 2018

Oncol Lett

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Abstract. Chemotherapy failure remains a challenge when treating patients with acute myeloid leukemia (AML), who often suffer from persistent or relapsed disease. The multidrug resistance (MDR) mediated by efflux transporters of the ATP binding cassette (ABC) superfamily is a major obstacle for successful chemotherapy. The present study aimed to elucidate whether the expression of ABC transporters was associated with prognostic factors and responses to chemotherapy in patients with AML, with particular focus on whether co-expression of multiple ABC transporters resulted in a worse prognosis. In the present study, the mRNA expression levels of ABC transporters ABCB1, ABCB4, ABCC1, ABCC4 and ABCG2 in bone marrow (BM) mononuclear cell (MNC) samples from 96 de novo patients with AML and in the peripheral blood (PB) MNC samples from 22 normal individuals were investigated using reverse transcription-quantitative polymerase chain reaction analysis. It was revealed that ABCB1, ABCC1, ABCC4 and ABCG2 were expressed at higher levels in patients with AML compared with normal individuals, whereas ABCB4 had a lower expression level. The expression of ABCB4 in patients with AML was significantly lower than in normal individuals (P<0.001). Patients risk status was associated with ABCB1 (P= 0.037), ABCC1 (P= 0.047), ABCC4 (P=0.015) and ABCG2 (P=0.027). The 4 genes were expressed a significantly higher levels in the poor response group compared with the good response group (ABCB1, P= 0.014; ABCC1, P= 0.021; ABCC4, P= 0.005; ABCG2, P= 0.009). The overexpression of the 4 ABC transporters and the complete remission rate were inversely correlated (P<0.001). These results suggest that the co-expression of multiple ABC transporters may contribute to a worse prognosis in AML.

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Section: Discussionmentioning

confidence: 84%

“…A recent study of 123 AML patients showed that patients with lower expression of the ABCB1 and ABCC1 genes had better OS and DFS compared with patients who had high expression of these genes (15). The predictive role of ABCC4 has been addressed in childhood AML (16).…”

Section: Discussionmentioning

confidence: 99%

Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia

Liu

Gong

et al. 2018

Oncol Lett

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“…However, it has lately been suggested as a cholesterol transporter in the brain, connected to amyloid-β peptide generation and Alzheimer’s disease, 40 and has been associated with the progression of acute myeloid leukemia. 41 The tight regulation of transporting substances across membranes ensures survival under challenging conditions and thus facilitates adaptation to new environments. Therefore, it seems rather not surprising to find members of the ABC1 subfamily stably expressed under altered gravity, which ultimately may be a new environmental condition that cells might have to adapt to.…”

Section: Discussionmentioning

confidence: 99%

Stability of gene expression in human T cells in different gravity environments is clustered in chromosomal region 11p15.4

et al. 2017

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In the last decades, a plethora of in vitro studies with living human cells contributed a vast amount of knowledge about cellular and molecular effects of microgravity. Previous studies focused mostly on the identification of gravity-responsive genes, whereas a multi-platform analysis at an integrative level, which specifically evaluates the extent and robustness of transcriptional response to an altered gravity environment was not performed so far. Therefore, we investigated the stability of gene expression response in non-activated human Jurkat T lymphocytic cells in different gravity environments through the combination of parabolic flights with a suborbital ballistic rocket and 2D clinostat and centrifuge experiments, using strict controls for excluding all possible other factors of influence. We revealed an overall high stability of gene expression in microgravity and identified olfactory gene expression in the chromosomal region 11p15.4 as particularly robust to altered gravity. We identified that classical reference genes ABCA5, GAPDH, HPRT1, PLA2G4A, and RPL13A were stably expressed in all tested gravity conditions and platforms, while ABCA5 and GAPDH were also known to be stably expressed in U937 cells in all gravity conditions. In summary, 10–20% of all transcripts remained totally unchanged in any gravitational environment tested (between 10−4 and 9 g), 20–40% remained unchanged in microgravity (between 10−4 and 10−2 g) and 97–99% were not significantly altered in microgravity if strict exclusion criteria were applied. Therefore, we suppose a high stability of gene expression in microgravity. Comparison with other stressors suggests that microgravity alters gene expression homeostasis not stronger than other environmental factors.

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“…With regard to AML, cell culture experiments demonstrated that AML cells are able to upregulate through epigenetic mechanisms the expression of a number of transporter proteins [53]. The mRNA expression for ABCA5, ABCB6, ABCC1, and ABCC3 has recently been reported to be upregulated in cells from 233 AML patients [54]. It is therefore likely that perturbed plasma lipid profiles in AML are related to intracellular changes in circulating AML cells through mechanisms involving multiple ABC transporters.…”

Section: Discussionmentioning

confidence: 99%

The plasma lipidome in acute myeloid leukemia at diagnosis in relation to clinical disease features

et al. 2017

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BackgroundEarly studies established that certain lipids were lower in acute myeloid leukemia (AML) cells than normal leukocytes. Because lipids are now known to play an important role in cell signaling and regulation of homeostasis, and are often perturbed in malignancies, we undertook a comprehensive lipidomic survey of plasma from AML patients at time of diagnosis and also healthy blood donors.MethodsPlasma lipid profiles were measured using three mass spectrometry platforms in 20 AML patients and 20 healthy blood donors. Data were collected on total cholesterol and fatty acids, fatty acid amides, glycerolipids, phospholipids, sphingolipids, cholesterol esters, coenzyme Q10 and eicosanoids.ResultsWe observed a depletion of plasma total fatty acids and cholesterol, but an increase in certain free fatty acids with the observed decline in sphingolipids, phosphocholines, triglycerides and cholesterol esters probably driven by enhanced fatty acid oxidation in AML cells. Arachidonic acid and precursors were elevated in AML, particularly in patients with high bone marrow (BM) or peripheral blasts and unfavorable prognostic risk. PGF2α was also elevated, in patients with low BM or peripheral blasts and with a favorable prognostic risk. A broad panoply of lipid classes is altered in AML plasma, pointing to disturbances of several lipid metabolic interconversions, in particular in relation to blast cell counts and prognostic risk.ConclusionsThese data indicate potential roles played by lipids in AML heterogeneity and disease outcome.General significanceEnhanced catabolism of several lipid classes increases prognostic risk while plasma PGF2α may be a marker for reduced prognostic risk in AML.

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Atp-Binding Casette Transporter Expression in Acute Myeloid Leukemia: Association with in Vitro Cytotoxicity and Prognostic Markers

Abstract: This comprehensive analysis suggests ABCC1, ABCC3, ABCB6 and ABCA5 as probable targets which can be modulated for improving chemotherapeutic responses.

Cited by 24 publications

References 41 publications

Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia

Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia

Stability of gene expression in human T cells in different gravity environments is clustered in chromosomal region 11p15.4

The plasma lipidome in acute myeloid leukemia at diagnosis in relation to clinical disease features

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