NF- B constitutes a potential therapeutic target in high-risk myelodysplastic syndrome

Abstract

Myelodysplastic syndrome (MDS) is a preneoplastic condition that frequently develops into overt acute myeloid leukemia (AML). The P39 MDS/AML cell line manifested constitutive NF-kappaB activation. In this cell line, NF-kappaB inhibition by small interfering RNAs specific for p65 or chemical inhibitors including bortezomib resulted in the down-regulation of apoptosis-inhibitory NF-kappaB target genes and subsequent cell death accompanied by loss of mitochondrial transmembrane potential as well as by the mitochondrial release of the caspase activator cytochrome c and the caspase-independent death effectors endonuclease G and apoptosis-inducing factor (AIF). Bone marrow cells from high-risk MDS patients also exhibited constitutive NF-kappaB activation similar to bone marrow samples from MDS/AML patients. Purified hematopoietic stem cells (CD34+) and immature myeloid cells (CD33+) from high-risk MDS patients demonstrated the nuclear translocation of the p65 NF-kappaB subunit. The frequency of cells with nuclear p65 correlated with blast counts, apoptosis suppression, and disease progression. NF-kappaB activation was confined to those cells that carried MDS-associated cytogenetic alterations. Since NF-kappaB inhibition induced rapid apoptosis of bone marrow cells from high-risk MDS patients, we postulate that NF-kappaB activation is responsible for the progressive suppression of apoptosis affecting differentiating MDS cells and thus contributes to malignant transformation. NF-kappaB inhibition may constitute a novel therapeutic strategy if apoptosis induction of MDS stem cells is the goal.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…For example, NF-kB activation and increased IKK activity are found in blasts and stem cells associated with acute myelogenous leukemia (AML) (Baumgartner et al, 2002). Consistent with this, NF-kB activation is detected in the bone marrow of patients with myelodysplastic syndrome (Braun et al, 2006), which is considered a precursor disease of AML. NF-kB is also activated in childhood acute lymphoblastic leukemia (Kordes et al, 2000), Hodgkin-Reed-Sternberg cells (Bargou et al, 1997), HTLV-1-positive leukemias (Hiscott et al, 2006), B-cell chronic lymphocytic leukemia (Furman et al, 2000;Zaninoni et al, 2003) and in primary blasts of CML (Kirchner et al, 2003).…”

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

“…ATM inhibition downregulates NF-kB and induces apoptosis in the MDS/AML cell line P39 The presence of activated, phosphorylated ATM (on serine 1981) was monitored in four different AML cell lines, KG1 (which normally does not harbor constitutive NF-kB activity), MOLM-13, MV4-11 and P39 (which all exhibit constitutive NF-kB activation; Braun et al, 2006a;Fabre et al, 2007). Only P39 cells exhibited a strong constitutive ATM phosphorylation, which could be inhibited by ATMI or KU55933 (Figures 2a and b).…”

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.…”

“…Early MDS associate blood cytopenias, which can be explained by an increased apoptotic turnover of hematopoietic stem cells and differentiating myeloid cells in a hypercellular bone marrow (BM). In early MDS, the clonal population that is undergoing apoptosis does not show any signs of NF-kB activation (Braun et al, 2006a). 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.…”

“…The IkBs are then polyubiquitinated and degraded by the proteasome, therefore allowing nuclear translocation of the NF-kB dimers and activation of their target genes. IKK can be activated by multiple intra-and extracellular stimuli (Karin et al, 2004), and the inhibition of IKK by inhibitors of the catalytic IKK subunits IKKa and IKKb can induce apoptosis in MDS and AML cell lines (Baumgartner et al, 2002;Braun et al, 2006a).…”