Tyrosine Kinase Inhibitor Independent Gene Expression Signature in CML Offers New Targets for LSPC Eradication Therapy.

Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. However, TKI do not eliminate the leukaemia stem cells (LSC), which can re-initiate the disease. Thus, finding new therapeutic targets in CML LSC is key to finding a curative treatment.

Correction: CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy.

The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain the survival of leukemic stem cells (LSCs).

Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia.

Inappropriate localization of proteins can interfere with normal cellular function and drive tumor development. To understand how this contributes to the development of acute myeloid leukemia (AML), we compared the nuclear proteome and transcriptome of AML blasts with normal human CD34 cells. Analysis of the proteome identified networks and processes that significantly affected transcription regulation including misexpression of 11 transcription factors with seven proteins not previously implicated in AML.

Exploring Stem Cell Heterogeneity in Chronic Myeloid Leukemia.

Until very recently, understanding the complexity of the stem cell (SC) compartment in both normal and leukemic hematopoiesis has been challenging due to the inability to separate and study normal and leukemic SCs at the single-cell level. Recent advances in cell-sorting techniques and single-cell technologies now make this possible, with the identification of a population of highly quiescent chronic myeloid leukemia (CML) SCs that is enriched following therapy with tyrosine kinase inhibitors (TKIs).

Cord Blood-Derived Quiescent CD34+ Cells Are More Transcriptionally Matched to AML Blasts Than Cytokine-Induced Normal Human Hematopoietic CD34+ Cells.

Acute myeloid leukemia (AML) is characterized by developmental arrest, which is thought to arise from transcriptional dysregulation of myeloid development programs. Hematopoietic stem and progenitor cells (HSPCs) isolated from human blood are frequently used as a normal comparator in AML studies. Previous studies have reported changes in the transcriptional program of genes involved in proliferation, differentiation, apoptosis, and homing when HSPCs were expanded ex vivo.

Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling.

Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean >10-fold) in >60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction of mitochondrial ROS was rarely observed.

The complexity of identifying cancer stem cell biomarkers.

The efficacy of glioma therapy can be considerably improved if it eliminates cancer stem cells (CSCs); however, to achieve this, CSCs markers are required. This study investigated the influence of micro-environmental changes on CSCs in hypoxic, serum deprived U87-MG and the corresponding control cells. Proteomic analysis produced a wide dataset, depicting the changes that occur at the proteomic level in the differentiated and undifferentiated U87-MG cell line.

A novel therapeutic strategy for the treatment of glioma, combining chemical and molecular targeting of hsp90a.

Hsp90a's vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90a was downregulated using the post-transcriptional RNAi strategy (sihsp90a) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90a, 17-AAG and concurrent sihsp90a/17-AAG (combined treatment).

Can hsp90alpha-targeted siRNA combined with TMZ be a future therapy for glioma?

Hsp90alpha's vital role in cell cycle progression and apoptosis together with its presence in gliomas and absence in normal tissue, make it a credible target for cancer therapy. Three sets of dsRNA oligos designed to align different regions of the hsp90alpha sequence were used to downregulate hsp90alpha. SiRNA 1, 2, and 3 resulted in significant levels of silencing of hsp90alpha after 48 hr treatment (p < .