scholarly journals Expression of some ATP-binding cassette transporters in acute myeloid leukemia

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Antonella Maria Salvia ◽  
Flavia Cuviello ◽  
Sabrina Coluzzi ◽  
Roberta Nuccorini ◽  
Immacolata Attolico ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Abc Transporters ◽  
Healthy Subjects ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Atp Binding ◽  
Atp Binding Cassette Transporters ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Hematopoietic cells express ATP binding cassette (ABC) transporters in relation to different degrees of differentiation. One of the known multidrug resistance mechanisms in acute myeloid leukemia (AML) is the overexpression of efflux pumps belonging to the superfamily of ABC transporters such as ABCB1, ABCG2 and ABCC1. Although several studies were carried out to correlate ABC transporters expression with drug resistance, little is known about their role as markers of diagnosis and progression of the disease. For this purpose we investigated the expression, by real-time PCR, of some ABC genes in bone marrow samples of AML patients at diagnosis and after induction therapy. At diagnosis, ABCG2 was always down-regulated, while an up regulated trend for ABCC1 was observed. After therapy the examined genes showed a different expression trend and approached the values of healthy subjects suggesting that this event could be considered as a marker of AML regression. The expression levels of some ABC transporters such as ABCC6, seems to be related to gender, age and to the presence of FLT3/ITD gene mutation.

Expression of three different ATP-binding cassette transporters and correlation to chemoresistance in acute myeloid leukemia

2014 ◽  
Vol 37 (1) ◽  
pp. e7-e10 ◽  
Author(s):  
D. Palaiologou ◽  
P. Panayiotidis ◽  
G. Papanikolaou ◽  
G. Georgiou ◽  
G. Boutsikas ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Atp Binding ◽  
Atp Binding Cassette Transporters ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Expression of the Human ATP-Binding Cassette Transporter Superfamily in Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1179-1179
Author(s):  
Maria Ho ◽  
Donna E. Hogge ◽  
Victor Ling
Keyword(s):  
Acute Myeloid Leukemia ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Normal Blood ◽  
Atp Binding ◽  
Normal Peripheral Blood ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Abstract Members of the ATP-Binding-Cassette (ABC) transporter superfamily of proteins are involved in resistance to multiple chemotherapeutic drugs ( Multidrug Resistance or MDR) in a variety of malignant cells including leukemic blasts. Overexpression of some ABC transporters has been demonstrated in acute myeloid leukemia (AML) and is associated with clinical MDR and failure of conventional chemotherapy, which occurs frequently in this leukemia. Recent studies have also demonstrated ABC transporter expression in primitive normal hematopoietic cells, including progenitors which may give rise to AML after malignant transformation. In this study we used quantitative Real-Time PCR to assess and compare the expression level of all 47 known human ABC transporters in AML blasts and normal peripheral blood. Peripheral blood blasts from 17 patients with newly-diagnosed AML who subsequently received conventional remission induction therapy with cytosine arabinoside and daunorubicin were studied; 11 of these subsequently achieved complete remission of their leukemia while the remaining 6 had chemotherapy refractory disease. Contrary to expectations, no consistent difference in mRNA levels was found between the chemotherapy responsive and refractory groups of patient samples for any ABC transporter, including known MDR-related members such as MDR-1 and BCRP. Profiling of the 47 ABC transporters in 12 normal peripheral blood samples (6 mobilized with G-CSF, 6 non-mobilized) showed that TAP1 and MRP3 were 3.3-fold (P = 0.032) and 24-fold (P = 0.012), respectively, higher in normal donors as compared to AML patients. ABCA7, ABCB8, MRP3, MRP7, ALDP, PMP70 and PMP69 were greater than 3-fold higher (P < 0.05) in G-CSF-mobilized as compared to steady state normal blood. These results suggest that levels of ABC transporter mRNA expression in AML blasts prior to chemotherapy are not predictive of treatment response. This raises questions regarding the role of ABC transporters in intrinsic as opposed to induced or acquired chemotherapy drug resistance, which in turn has important implications in clinical usage of ABC-reversal agents. In addition, we identified expression of a variety of ABC transporters in both AML blasts and normal blood cells suggesting that this class of transporter proteins may have importance in both normal and malignant hematopoiesis.

ATP-binding cassette (ABC) proteins in untreated acute myeloid leukemia (AML) in patients 60 years and older (CALGB 9760)

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 6551-6551
Author(s):  
M. R. Baer ◽  
J. S. Shoemaker ◽  
R. Barrier ◽  
N. W. Cuviello ◽  
K. L. O’Loughlin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Atp Binding ◽  
Abc Proteins ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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