Regulation of CLL survival by hypoxia‐inducible factor and its target genes

Abstract

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is characterized by the progressive accumulation of small mature CD5+B lymphocytes in the peripheral blood, lymphoid organs, and bone marrow (BM). The main feature of the disease is decreased apoptosis, resulting in the pathologic accumulation of these malignant cells. Appropriate cellular responses to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, are ultimately regulated by the transcription factor, hypoxia‐inducible factor (HIF). Unlike their normal counterparts, CLL cells express HIF‐1α even under normoxia. In addition, overexpression of HIF‐1α has been observed in leukemic cells in BM specimens from CLL patients. The HIF transcription factor has been implicated in controlling the expression of a wide variety of genes implicated in apoptosis, angiogenesis, invasion, and metastasis. This review describes pathways regulating CLL survival with a focus on HIF‐1α and its target genes, MIF and Midkine (MK), and the potential cross‐talk between these factors.

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

“…15 HIF-1a and HIF-2a are the 2 main transcription factors regulated by hypoxia that support tumor progression by activating specific genetic programs. 16,17 In vivo evidence confirms that hypoxia acts partly through the activation of A2A adenosine receptor signaling. 18,19 Although circulating CLL cells constitutively express a transcriptionally active HIF-1a, 20 its role in regulating CLL survival and its mechanisms of action remain incompletely understood.…”

HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

“…Because leukemia cell death induced by EZN-2208 in BM and spleen of xeno-and allotransplanted mice could not account for the extent of spleen weight reduction and decreased BM infiltration (Figures 4 and 5), and because HIF-1a regulates genes involved in cell adhesion in CLL cells (Figure 1), we asked whether EZN-2208 induced release of CLL cells from protective niches, thus causing their further elimination by cell death upon mobilization. 37 To measure cell mobilization in a confined ex vivo system, small fragments of leukemic spleens were maintained for 48 hours in bioreactor-based rotary cell cultures, which preserve organ architecture and ensure long-term cell viability. 38 Ex vivo treatment with EZN-2208 induced specific mobilization of CLL cells from leukemic spleens into the culture supernatant without affecting the release of other cell types ( Figure 5F).…”

The Skewed Balance Between Tregs and Th17 in Chronic Lymphocytic Leukemia

“…The increased frequency of different Treg subsets is associated with a downregulation of Th17 and Tc17 cells The imbalance between mRNA level of FoxP3 and RORγt [94] The frequency of Th17 cells adversely correlated with Tregs [98] Lenalidomide therapy induces Th17 and inhibits Tregs [93] Imbalanced frequency of Treg/Th17 in CLL patients [75,103] Malignant B cells inhibit IL-17 producing T cells and stimulate Treg development [91] and is associated with disease progression [115], it seems that HIF-1 cannot be considered as worthy tool for downregulation of Treg and expansion of Th17 cells.…”