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

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.

The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia

“…The CD44 hyaluronic acid receptor is involved in homing of leukemic cells. Crosstalk existing between the CXCR4/SDF-1 axis and CD44 in normal hematopoietic cells can block acute myeloid leukemia cell homing [50]. In this study, we found that shikonin treatment decreased the expression of CXCR4, SDF-1, and CD44.…”

Leukemic stem cells: identification and clinical application

“…CD33 is, next to leukemic cells, also present on most HSC, on mature and immature myeloid cell and on various progenitors [52], possibly underlying toxicities as found in earlier studies [53]. Anti-CD123 therapy may have similar disadvantages [6], while results of clinical trials targeting newer discovered surface markers more specific for LSC (including CCL-1 [54,55], TIM3 [55][56][57], CD96 [58]), will provide important insights in validity of therapies targeting immunophenotypic markers. Next to specificity, the design of the antibody in terms of conjugates is of importance for effectiveness.…”

A Novel Tissue and Stem Cell Specific TERF1 Splice Variant Is Downregulated in Tumour Cells

“…The above data indicated however that TERF1-tsi expression may be restricted to a subset of stem cells in a given tissue, making it difficult to detect. Thus we analyzed its expression in CD34-enriched population of human hematopoietic stem cells (HSCs), CD34-enriched population of human liver cells, human hepatocytes, human prostate epithelial cells, and the CD34-positive human acute myelogenous leukemia cell line KG-1 [37]. Both semi-quantitative PCR and RT-qPCR data clearly show the presence of TERF1-tsi mRNA in the CD34-enriched HSCs (Figure 13).…”