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GEN News Highlights : Aug 14, 2012
New Target for Acute Myeloid Leukemia Found
Scientists have identified a class II (nonclustered) homeobox gene as a potential prognostic and therapeutic target for acute myeloid leukemia (AML). The gene, known as H2.0-like homeobox (HLX), is expressed at elevated levels in AML patients, and correlates with poor survival, according to a team at Albert Einstein College of Medicine. Moreover, the researchers found that knocking down HLX in both human and mouse AML cells dampened cell proliferation, while mice transplanted with HLX-knockout human or mouse AML cells survived much longer than those transplanted with animals receiving unaltered cells.
Ulrich Steidl, Ph.D., and colleagues’ prior analysis of preleukemic hematopoietic stem and progenitor cells (HSPCs) in a murine model of AML had found that HLX was upregulated four-fold compared with wild-type HSPCs, and they postulated that the gene might be involved in malignant transformation. Moving on to look more closely at the gene’s role in AML, they found that overexpression of HLX in mouse bone marrow cells impaired hematopoietic reconstitution following transplantation into irradiated recipient mice. The loss of functional hematopoietic stem cells associated with HLX overexpression was accompanied by the development of abnormal progenitors that failed to differentiate into normal blood cells, but proliferated as abnormal white blood cells.
Importantly, when the researchers analyzed HLX expression data from over 350 AML patients they found that 87% overexpressed HLX, and those patients with the highest expression levels had the poorest survival. Conversely, knockdown of HLX in both human and mouse AML cells using a targeted shRNA led to reduced cell proliferation, and increased survival following transplantation into experimental mice. Gene set enrichment analysis (GSEA) showed that the expression of nearly 400 genes was changed as a result of HLX knockdown in AML cells, in comparison with unmodified AML cells. Genes involved in leukocyte differentiation, cell activation, and cell proliferation were among those most significantly affected. “We specifically found that several key genes involved in the regulation of cell cycle and proliferation, cell death, and myeloid differentiation were significantly changed upon HLX downregulation,” the authors write.
Further assays indicated that mechanistically HLX regulates a transcriptional program, including PAK1 and BTG1, which controls cellular differentiation and proliferation. In fact downregulating PAK1 and upregulating BTG1 (through ectopic expression) both had the same effects as knocking down HLX.
Knockdown of HLX in human AML cells also led to reproducible changes in gene expression, and a profile that could be used to predict overall survival. Interestingly, this HLX-induced prognostic in human cells also featured PAK1. “The correlation of HLX and PAK1 expression levels in the murine HLX knockdown model and in patients with AML, together with the observed induction of Pak1 expression upon HLX overexpression in stem cells, strongly suggest that PAK1 is a downstream target of HLX and critically mediates, at least in part, the leukemia-promoting effects of HLX in patients in vivo,” the researchers state. “HLX expression levels may be utilized to predict clinical outcome and improve risk stratification ... inhibition of HLX may be a promising strategy for treatment of patients with AML.”
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