Oncotarget

Research Papers:

Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1

Noureldien H.E. Darwish, Thangirala Sudha, Kavitha Godugu, Osama Elbaz, Hasan A. Abdelghaffar, Emad E.A. Hassan, Shaker A. Mousa _

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Oncotarget. 2016; 7:57811-57820. https://doi.org/10.18632/oncotarget.11063

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Abstract

Noureldien H.E. Darwish1,2, Thangirala Sudha2, Kavitha Godugu2, Osama Elbaz1, Hasan A. Abdelghaffar1, Emad E.A. Hassan1, Shaker A. Mousa2

1Faculty of Medicine, Mansoura University, Mansoura, Egypt

2The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA

Correspondence to:

Shaker A. Mousa, email: shaker.mousa@acphs.edu

Keywords: acute myeloid leukemia, leukemic stem cells, chronic myeloid leukemia, chronic myelomonocytic leukemia, PTC-209

Received: March 23, 2016     Accepted: July 19, 2016     Published: August 05, 2016

ABSTRACT

Acute myeloid leukemia (AML) patients show high relapse rates and some develop conventional chemotherapy resistance. Leukemia Stem Cells (LSCs) are the main player for AML relapses and drug resistance. LSCs might rely on the B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) in promoting cellular proliferation and survival. Growth of LSCs in microenvironments that are deprived of nutrients leads to up-regulation of the signaling pathways during the progression of the disease, which may illustrate the sensitivity of LSCs to inhibitors of those signaling pathways as compared to normal cells. We analyzed the expression of LSC markers (CD34, CLL-1, TIM-3 and BMI-1) using quantitative RT-PCR in bone marrow samples of 40 AML patients of different FAB types (M1, M2, M3, M4, M5, and M7). We also studied the expression of these markers in 2 AML cell lines (Kasumi-1 and KG-1a) using flow cytometry and quantitative RT-PCR. The overexpression of TIM-3, CLL-1, and BMI-1 was markedly correlated with poor prognosis in these patients. Our in vitro findings demonstrate that targeting BMI-1, which markedly increased in the leukemic cells, was associated with marked decrease in leukemic burden. This study also presents results for blocking LSCs’ surface markers CD44, CLL-1, and TIM-3. These markers may play an important role in elimination of AML. Our study indicates a correlation between the expression of markers TIM-3, CLL-1, and especially of BMI-1 and the aggressiveness of AML and thus the potential impact of prognosis and therapies that target LSCs on improving the cure rates.


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