Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics.

Håkon Reikvam

doi:10.3390/cells9071677

Abstract

Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.

Highlights

Acute myelogenous leukemia (AML) is a heterogeneous and aggressive malignancy characterized by bone marrow accumulation of immature leukemic blasts that suppress normal hematopoiesis [1].The median age at the time of diagnosis is 65–70 years [1], and for younger patients receiving the most intensive therapy, the median long-term AML-free survival is 45–50% [2]
We identified a significant impact of nuclear factor-κB (NF-κB) inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs
NF-κB is an important transcription factor involved in AML leukemogenesis, and it is regarded as a potential therapeutic target

Summary

Introduction

Acute myelogenous leukemia (AML) is a heterogeneous and aggressive malignancy characterized by bone marrow accumulation of immature leukemic blasts that suppress normal hematopoiesis [1].The median age at the time of diagnosis is 65–70 years [1], and for younger patients receiving the most intensive therapy, the median long-term AML-free survival is 45–50% [2]. The average survival for those patients receiving supportive therapy alone is only 2–4 months, and very few survive longer than one year [3]. The NF-κB family of transcription factors was identified more than 30 years ago as a binding interactor for the κ light chain enhancer in B-lymphocytes [7]. This complex is activated by several stimuli, including pro-inflammatory cytokines, mitogens, growth factors, and stress-inducing agents [8,9,10]

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