Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells

Abstract

Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leuke-mic stem cells (LSCs), have been documented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found in many leukemic populations. Because these cells are likely to be critical for the genesis and perpetu-ation of leukemic disease, the present studies sought to characterize unique molecular properties of the LSC population , with particular emphasis on the transcription factor, nuclear factor-B (NF-B). Previous experiments have shown that unstimulated human CD34 progenitor cells do not express NF-B. In contrast , primary AML CD34 cells display readily detectable NF-B activity as assessed by electrophoretic mobility shift assay and gene expression studies. Furthermore , detailed analyses of enriched AML stem cells (CD34 /CD38 /CD123) indicate that NF-B is also active in the LSC population. Given the expression of NF-B in leukemic, but not normal primitive cells, the hypothesis that inhibition of NF-B might induce leukemia-specific apoptosis was tested by treating primary cells with the proteasome inhibitor MG-132, a well-known inhibitor of NF-B. Leukemic CD34 /CD38 cells displayed a rapid induction of cell death in response to MG-132, whereas normal CD34 /CD38 cells showed little if any effect. Taken together, these data indicate that primitive AML cells aberrantly express NF-B and that the presence of this factor may provide unique opportunities to preferentially ablate LSCs. (Blood. 2001;98: 2301-2307)

Inhibition of NEMO, the regulatory subunit of the IKK complex, induces apoptosis in high-risk myelodysplastic syndrome and acute myeloid leukemia

“…Several studies have characterized the activation level of NF-kB in the BM of AML patients and more precisely in LSC (Guzman et al, 2001). Constitutively active NF-kB (mostly p50/p65) has been detected in premalignant and malignant cells derived from patients with high-risk MDS (Braun et al, 2006a) and AML (Guzman et al, 2001). Targeting NF-kB in these hematopoietic malignancies leads to apoptosis, corroborating the role of NF-kB in the survival and clonal expansion of malignant cells.…”

“…Latestage MDS, which is coupled to NF-kB activation, is marked by a progressive increase of immature cells and frequent transformation to acute myeloid leukemia (AML), presumably owing to a progressive suppression of programmed cell death and increased clonal proliferation. AML represents a heterogeneous group of clonal stem cell malignancies arising from so-called leukemic stem cells (LSC) (Guzman et al, 2001(Guzman et al, , 2002Estrov et al, 2003). LSC give rise to leukemic myeloid blasts arrested at different (Guzman et al, 2001) maturation steps.…”

“…AML represents a heterogeneous group of clonal stem cell malignancies arising from so-called leukemic stem cells (LSC) (Guzman et al, 2001(Guzman et al, , 2002Estrov et al, 2003). LSC give rise to leukemic myeloid blasts arrested at different (Guzman et al, 2001) maturation steps. Several studies have characterized the activation level of NF-kB in the BM of AML patients and more precisely in LSC (Guzman et al, 2001).…”

“…LSC give rise to leukemic myeloid blasts arrested at different (Guzman et al, 2001) maturation steps. Several studies have characterized the activation level of NF-kB in the BM of AML patients and more precisely in LSC (Guzman et al, 2001). Constitutively active NF-kB (mostly p50/p65) has been detected in premalignant and malignant cells derived from patients with high-risk MDS (Braun et al, 2006a) and AML (Guzman et al, 2001).…”

Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα

“…NF-kB has been found constitutively activated in series of human cell lines and samples derived of solid or hematopoietic tumors such as chronic myeloid leukemia (CML) (Kirchner et al, 2003), acute leukemias (Kordes et al, 2000;Guzman et al, 2001;Baumgartner et al, 2002), multiple myelomas (Feinman et al, 1999) and lymphomas of various types (Davis et al, 2001;Savage et al, 2003). In hematopoietic tumors, NF-kB activation may occur through amplifications, mutations and/or chromosomal rearrangements of genes encoding NF-kB subunits themselves or relays of the pathway as the Bcl10 and Malt1 proteins, which link the antigen receptors to the IKK complex in normal lymphoid cells (Rayet and Gelinas, 1999;Weil and Israel, 2004).…”