Abstract
Hypoxia inducible transcription factors (HIFs) are the main regulators of adaptive responses to hypoxia and are often activated in solid tumors, but their role in leukemia is less clear. In acute myeloid leukemia (AML), in particular, controversial new findings indicate that HIF-1α can act either as an oncogene or a tumor suppressor gene, and this may depend on the stage of leukemia development and/or the AML sub-type.In this study, we find that HIF-1α promotes leukemia progression in the acute monocytic leukemia sub-type of AML through activation of an invasive phenotype. By applying a list of validated HIF-1α-target genes to different AML sub-types, we identified a HIF-1α signature that typifies acute monocytic leukemia when compared with all other AML sub-types. We validated expression of this signature in cell lines and primary cells from AML patients. Interestingly, this signature is enriched for genes that control cell motility at different levels. As a consequence, inhibiting HIF-1α impaired leukemia cell migration, chemotaxis, invasion and transendothelial migration in vitro, and this resulted in impaired bone marrow homing and leukemia progression in vivo. Our data suggest that in acute monocytic leukemia an active HIF-1α-dependent pro-invasive pathway mediates the ability of leukemic cells to migrate and invade extramedullary sites and may be targeted to reduce leukemia dissemination.
Highlights
Acute myeloid leukemia (AML) represents almost 80% of all adult acute leukemia and is a heterogeneous disorder of the hematopoietic system caused by a number of genetic alterations and characterized by uncontrolled cell proliferation, escape from apoptosis and block of myeloid differentiation [1, 2]
We found that besides acute myeloid leukemia (AML)-M3, which we had previously identified as an AML sub-type with specific up-regulation of hypoxia signaling [24, 28], AML-M5 patients display specific up-regulation of a number of Hypoxia inducible transcription factors (HIFs)-1α-target genes implicated in cell migration, invasion and transendothelial migration
Recent studies have suggested that in AML HIF-1α may act as an oncogene or a tumor suppressor gene depending on the AML sub-type [30]
Summary
Acute myeloid leukemia (AML) represents almost 80% of all adult acute leukemia and is a heterogeneous disorder of the hematopoietic system caused by a number of genetic alterations and characterized by uncontrolled cell proliferation, escape from apoptosis and block of myeloid differentiation [1, 2]. Acute monocytic leukemia is the M5 sub-type of acute myeloid leukemia (AML-M5) according to the French-American-British (FAB) classification [3, 4]. AML-M5 is characterized www.impactjournals.com/oncotarget by hyperleukocytosis, intravascular coagulation and a propensity to infiltrate extramedullary sites [7,8,9]. Beyond the phenotypic and clinical characterization, AML-M5 encompasses a class of genetically heterogeneous diseases with different mutations and chromosomal translocations. Frequent genetic aberrations include translocations involving the MLL gene on chromosome 11q23, and mutations in NPM1, FLT3, NRAS and DNMT3A [10,11,12,13, 9], with NPM1 mutations associated with favorable prognosis, and FLT3 and DNMT3A mutations and MLL rearrangements associated with adverse prognosis [14]
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