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Background/Aims: Acute myeloid leukemia (AML) is a heterogeneous clonal disease and patients with AML who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. This study aims to identify novel targets for explaining the dilemmas. Methods: We analyzed four microarray gene expression profiles to investigate changes in whole genome expression associated with FLT3-ITD mutation. Results: We identified 22 differentially expressed genes which are commonly expressed among all four profiles. Kaplan-Meier analysis of the dataset GSE12417 revealed that low expression of AHSP, EPB42, GYPC and HEMGN predicted poor prognosis (AHSP: P=0.0317, HR=1.894; EPB42: P=0.0382, HR=1.859; GYPC: P=0.0015, HR=2.051; HEMGN: P=0.0418, HR=1.838 in GSE12417 test cohort; AHSP: P=0.0279, HR=1.548; EPB42: P=0.0398, HR=1.505; GYPC: P=0.0408, HR=1.501; HEMGN: P=0.0143, HR=1.630 in GSE12417 validation cohort). When patients were FLT3-ITD positive, the expression of FLT3 was significantly increased (all P<0.05 in four profiles), and correleation analysis of four profiles revealed that the expression of the four candidate genes negatively correlated with FLT3 expression. Conclusions: Our findings suggest that AHSP, EPB42, GYPC and HEMGN may be suitable biomarkers for diagnostic or therapeutic strategies for FLT3-ITD-positive AML patients. [ABSTRACT FROM AUTHOR]

Summary: It is well known that the mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. Thus, P-gp has been looked as a well established mediator of MDR and it became a therapeutic target for circumventing multidrug resistance. However, the mechanism of adjusting the expression of P-gp is not clear yet. The results of the effect of genetic polymorphism on P-gp expression and function remain conflicting. More recently, studies on the regulation of MDR1 has widened to examine the role of epigenetics and some new results were found to support the effect of epigenetic variance in vitro. It is hence hypothesized that epigenetic variants play more important roles than genetic polymorphism, thus adjusting the epigenetic factors could alter the expression of MDR, leading to the reverse of MDR. And it is further hypothesized that histone deacetylase inhibitors could be another strategy to overcome MDR. The mechanism may include a bidirectional modulation of P-gp by histone deacetylase inhibitors. [Copyright &y& Elsevier]

Abstract: Both the occurrence and recurrence of acute leukemia (AL) might suggest the presence of leukemia stem cells. Side population (SP) cells, exhibiting stem cell-like properties, express ABCG2 (breast cancer resistance protein [BCRP]). This study revealed that over-expression of ABCG2 in Jurkat and HL60 cells led to an increased SP fraction, up-regulated levels of phosphorylated-PI3K and phosphorylated-Akt, and enhanced drug resistance, all of which could be attenuated by treatment with either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin. ABCG2 expression and SP cell counts were further characterized in 222 adult AL patients at three disease stages: upon diagnosis, at remission and at refractory/relapse (R/R), while 10 healthy donors served as the normal controls. Only a small fraction of the ABCG2+population (0.05–12.3%) and SP cells (0.02–1.60%) were observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. In the normal control population, the SP cell fraction represented a statistically higher percentage of total cells compared to the fraction of SP cells upon diagnosis or relapse in both AML and ALL. In addition, we demonstrated that ABCG2 expression and SP cell ratios can be upregulated by the inactivation of phosphatase and tensin homolog (PTEN) protein, achieved in this study by removing inhibition of the PI3K/Akt pathway. Collectively, this study suggests that the PTEN/PI3K/Akt pathway up-regulates ABCG2 expression and the SP cell population and is a potential AL-specific treatment target worth investigating further. [Copyright &y& Elsevier]