Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.
A new mouse in which an IRES-GFP cassette is knocked-in to the Evi1 locus reveals that HSC long-term multilineage repopulating activity specifically segregates with expression of the Evi1 transcription factor.
Induced pluripotent stem cells (iPSCs)can be generated by the expression of defined transcription factors not only from normal tissue, but also from malignant cells. Cancer-derived iPSCs are expected to provide a novel experimental opportunity to establish the disease model. We generated iPSCs from imatinib-sensitive chronic myelogenous leukemia (CML) patient samples. Remarkably, the CML-iPSCs were resistant to imatinib although they consistently
Ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor that plays an essential role in the regulation of hematopoietic stem cells. Aberrant expression of Evi-1 has been reported in up to 10% of patients with acute myeloid leukemia and is a diagnostic marker that predicts a poor outcome. Although chromosomal rearrangement involving the Evi-1 gene is one of the major causes of Evi-1 activation, overexpression of Evi-1 is detected in a subgroup of acute myeloid leukemia patients without any chromosomal abnormalities, which indicates the presence of other mechanisms for Evi-1 activation. In this study, we found that Evi-1 is frequently up-regulated in bone marrow cells transformed by the mixed-lineage leukemia ( IntroductionThe ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor that plays an essential role in the proliferation and maintenance of hematopoietic stem cells (HSCs). 1-3 There are 2 major alternative forms generated from the Evi-1 gene, Evi-1a and Mds1-Evi-1 (also called Evi-1c). Mds1-Evi-1 is a fusion variant of Evi-1 generated through intergenic splicing with Mds1, 4 a gene located approximately 140 and 500 kb upstream of Evi-1 in the human and mouse genome, respectively. In contrast to Evi-1a, Mds1-Evi-1 possesses the PRDI-BF1-RIZ1 homologous (PR) domain in the N-terminus, which regulates oligomerization of the Evi-1 proteins. 5 Both Evi-1a and Mds1-Evi-1 are normally coexpressed in several developing and adult tissues, 6 and differences in the normal function between these proteins remain to be elucidated. Like all other PR domain proteins, Evi-1 contains several zinc finger motifs. They are grouped into N-terminal 7 and C-terminal 3 clusters, which are called the first and second zinc finger domain, respectively. 7,8 Between these 2 zinc finger domains lie the C-terminal binding protein (CtBP) domain and the repression domain. The first zinc finger, the repression, and the CtBP-binding domains exhibit a growth-promoting effect by blocking transforming growth factor- signaling. 9 The first zinc finger domain also exhibits an antiapoptotic effect by repressing c-Jun N-terminal kinase signaling. 10 The second zinc finger domain stimulates proliferation by increasing activator protein-1 activity. 11 Thus, Evi-1 possesses diverse functions as an oncoprotein.Aberrant expression of EVI-1 frequently has been found in myeloid leukemia and in several solid tumors and is associated with poor prognosis of patients with leukemia. 12-15 Rearrangements of chromosome 3q26, which contains the EVI-1 gene, lead to overexpression of EVI-1 and are implicated in the development or progression of high-risk acute myeloid leukemia (AML). 16 Importantly, EVI-1 is also highly expressed in a subgroup of AML patients without 3q26 rearrangements, 12 which indicates the presence of other mechanisms of EVI-1 activation. Recently, several clinical studies revealed a positive correlation between EVI-1 (both EVI-1a and MDS1-EVI-1) overexpression and rearrangements of the mixed-lineage ...
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