Essential role of Jun family transcription factors in PU.1 knockdown–induced leukemic stem cells

2006 ◽  
Vol 38 (11) ◽  
pp. 1269-1277 ◽  
Author(s):  
Ulrich Steidl ◽  
Frank Rosenbauer ◽  
Roel G W Verhaak ◽  
Xuesong Gu ◽  
Alexander Ebralidze ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Essential Role ◽  
Leukemic Stem Cells

scholarly journals Essential role of PU .1 in maintenance of mixed lineage leukemia‐associated leukemic stem cells

2015 ◽  
Vol 106 (3) ◽  
pp. 227-236 ◽  
Author(s):  
Yukiko Aikawa ◽  
Kazutsune Yamagata ◽  
Takuo Katsumoto ◽  
Yutaka Shima ◽  
Mika Shino ◽  
...  
Keyword(s):  
Stem Cells ◽  
Essential Role ◽  
Mixed Lineage Leukemia ◽  
Leukemic Stem Cells

scholarly journals Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment

2020 ◽  
Vol 21 (17) ◽  
pp. 6247
Author(s):  
Yongsheng Ruan ◽  
Hye Na Kim ◽  
Heather Ogana ◽  
Yong-Mi Kim
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Stromal Cells ◽  
Critical Role ◽  
Neoplastic Disease ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem ◽  
Disease Therapy ◽  
Wnt Pathways

Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and noncanonical Wnt pathways play a critical role in the maintenance of normal hematopoietic stem cells (HSC) and LSCs. In this review, we summarize recent findings on the role of Wnt signaling in leukemia and its microenvironment and provide information on the currently available strategies for targeting Wnt signaling.

scholarly journals Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy

Epigenomes ◽  
2020 ◽  
Vol 4 (1) ◽  
pp. 3
Author(s):  
Richard Momparler ◽  
Sylvie Côté ◽  
Louise Momparler
Keyword(s):  
Stem Cells ◽  
Gene Silencing ◽  
Epigenetic Therapy ◽  
Proliferative Potential ◽  
Primary Role ◽  
Leukemic Stem Cells ◽  
Self Renewal ◽  
Epigenetic Gene Silencing ◽  
Idh Mutations

Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires the complete eradication of the leukemic stem cells (LSCs). One aspect of LSCs that is poorly understood is their low frequency in the total population of leukemic cells in AML patients. After each cell division of LSCs, most of the daughter cells lose their capacity for self-renewal. Investigations into the role of Isocitrate dehydrogenase (IDH) mutations in AML provide some insight on the regulation of the proliferation of LSCs. The primary role of IDH is to convert isocitrate to alpha-keto-glutarate (α-KG). When IDH is mutated, it converts α-KG to 2-hydroxyglutarate (2-HG), an inhibitor of the TET pathway and Jumonji-C histone demethylases (JHDMs). The demethylating action of these enzymes removes the epigenetic gene-silencing markers, DNA methylation, H3K27me3 and H3K9me2 and can lead to the differentiation of LSCs. This enzymatic action is blocked by 2-HG in mutated IDH (mut-IDH) AML patients, who can be induced into remission with antagonists of 2-HG. These observations suggest that there exists in cells a natural enzymatic mechanism that uses demethylation to reverse epigenetic gene-silencing, leading to a loss of the self-renewal capacity of LSCs. This mechanism limits the proliferative potential of LSCs. Epigenetic agents that inhibit DNA and histone methylation exhibit a synergistic antineoplastic action on AML cells. It is possible that the therapeutic potential of this epigenetic therapy may be enhanced by demethylation enzymes, resulting in a very effective treatment for AML.

Gfi1b-A Novel Tumor Suppressor In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3795-3795
Author(s):  
Lacramioara Botezatu ◽  
Judith Hönes ◽  
Amos Zeller ◽  
Lars C. Michel ◽  
Andre Görgens ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem ◽  
Blast Cells ◽  
Leukemia Development ◽  
Acute Myeloid

Abstract The proper differentiation of hematopoietic stem cells is regulated by a concert of different so called transcription factors. Growth Factor Independence 1b (Gfi1b) is a repressing transcription factor, which is pivotal for the proper emergence and maturation of erythrocytes and platelets. Furthermore, Gfi1b controls quiescence as well as cell cycle progression of hematopoietic stem cells and early progenitor cells. It has been shown for other transcription factors that a disturbed function of these transcription factors can be the basis of malignant diseases such acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). MDS is characterized by disturbed differentiation of one or several hematopoietic lineages. The accumulation of malignant blast cells, which are arrested in their development, is a key feature of AML. Since transcription factors play a role in AML development, we sought to investigate whether Gfi1b might also play a role in the development and progression of AML. Based on published gene expression arrays and own patient samples, we observed that Gfi1b is expressed at a lower level in leukemic blasts and leukemic stem cells compared to the non-malignant control cells. We correlated Gfi1b expression level in blast cells of patients from Essen and we found out that patients with high Gfi1b levels had a poor prognosis and an increased risk of relapse. In contrast low levels of Gfi1b expression were associated with a good prognosis. To test how different levels of Gfi1b might influence initiation of AML we have mouse strains available expressing Gfi1b at different expression levels. We have Gfi1b wt mice with one allele of Gfi1b deleted (Gfi1b het) and Gfi1b conditional mice, in which the expression of Gf1b (Mx Cre tg Gfi1b fl/fl) can be abrogated after injecting these mice with pIpC. To explore the role of Gfi1b in leukemia development, we used different murine AML models, resembling human leukemia. First these mice were crossed with Nup98HoxD13 transgenic mice, a mouse strain that develops a disease similar to the human MDS. We observed that Gfi1b heterozygosity (n=15) accelerated AML development (p=0,03) compared to wt mice (n=16). More importantly, complete absence of Gfi1b (n=8) results in a substantially earlier onset of AML, with a median survival time of about 50 days (p=0.002). To confirm our findings, we used a different murine AML model. Recurrent so called oncofusion proteins such as AML1-Eto9a, CBFbeta-Myh11 or MLL-AF9 are characteristic for certain subtypes of AML. We transduced Lineage negative (Lin-) bone marrow cells from wt, Gfi1b heterozygous (Gfi1b het) and Gfi1b deficient (MxCre Gfi1b fl/fl) mice with retroviruses encoding either AML1-Eto9a or MLL-AF9 oncofusion -proteins. Transduced Gfi1b heterozygous or Gfi1b deficient cells generated more colonies and higher cell number than wt transduced cells. We also used mice transgenically expressing CBFbeta-Myh11. Deletion of Gfi1b accelerated leukemia formation in these mice compared to mice in which Gfi1b was still expressed. On a molecular level, we found that loss of Gfi1b leads to increased levels of ROS level. It has been shown by other groups, that increased levels of Gfi1b contribute to leukemia development. In addition, Gfi1b represses the expression of Integrin beta 3 (ITGB3). Absence of Gfi1b leads to higher expression level of ITGB3. ITGB3 has been shown to promote growth and expansion of leukemic stem cells, which play an important role in AML development. Thus we report here that Gfi1b acts as a novel tumor suppressor in AML development. Disclosures: No relevant conflicts of interest to declare.

Role of mature leukemic cells in the amplification of leukemic stem cells in a murine model

1995 ◽  
Vol 60 (5) ◽  
pp. 652-659
Author(s):  
Ulrich Dührsen ◽  
Gabriele Knieling ◽  
Dieter Kurt Hossfeld
Keyword(s):  
Stem Cells ◽  
Murine Model ◽  
Leukemic Cells ◽  
Leukemic Stem Cells

scholarly journals Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors

2016 ◽  
Vol 291 (21) ◽  
pp. 11148-11160 ◽  
Author(s):  
Shuyang Yu ◽  
Fengyin Li ◽  
Shaojun Xing ◽  
Tianyan Zhao ◽  
Weiqun Peng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Leukemic Stem Cells

Elucidating the role of the long non-coding RNA dancr in leukemic stem cells in acute myeloid leukemia (AML)

2017 ◽  
Vol 53 ◽  
pp. S124
Author(s):  
Marius Bill ◽  
Malith Karunasiri ◽  
Matthew Burke ◽  
Allison Walker ◽  
Stefano Volinia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cells ◽  
Non Coding Rna ◽  
Long Non Coding Rna ◽  
Acute Myeloid

scholarly journals The Role of NADPH Oxidase 2 in Normal and Malignant Hematopoiesis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1079-1079
Author(s):  
Biniam Adane ◽  
Haobin Ye ◽  
Shanshan Pei ◽  
Nabilah Khan ◽  
Mohammad Minhajuddin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Advisory Board ◽  
Leukemic Cells ◽  
Leukemic Stem Cells ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Knock Out

Abstract NADPH dependent oxidase 2 (NOX2) is the founding member of a family of multimeric, oxido-reductase enzymes that catalyze the production of superoxides by transferring a single electron from the cofactor NADPH to molecular oxygen. It is primarily utilized in neutrophils and macrophages to generate copious amount of reactive oxygen species (ROS) to facilitate the neutralization of engulfed particulates during phagocytosis. In sharp contrast to this specialized function however, recent evidence implies a non-phagocytic role for NADPH oxidases in which physiologic levels of ROS generated by these enzymes modulate key signaling proteins and transcription factors to exert profound biological effects. Based on this information we decided to investigate the potential role of NOX2 in normal and leukemic stem cells. Using transgenic NOX2 knock out mice, genetically defined murine models of myeloid leukemia and primary human acute myeloid leukemia (AML) specimens, we show that NOX2 is critical for the proper function of normal and malignant hematopoietic stem cells. In silico analysis using published transcriptional profiles of hematopoietic populations revealed that multiple subunits of the NOX2 complex are expressed at low levels in hematopoietic stem cells (HSCs) and at relatively higher levels in multipotent progenitors (MPPs). Next, we characterized the different hematopoietic compartments from age and sex matched wild type (WT) and transgenic NOX2 knock out (KO) mice. Our studies revealed that in the bone marrow of KO mice, a subset of multipotent progenitor populations (MPP2 & MPP3), which often have biased myelo-erythroid output are markedly expanded relative to their wild type counterparts. Consistently, we found increased levels of granulocytes and monocytes in the peripheral circulation of NOX2 KO mice. To test whether NOX2 has a functional, biological role in the self-renewal of HSCs, we performed competitive transplantation assays using equal numbers of whole BM cells from WT and KO mice to co-repopulate lethally irradiated hosts. Analysis of engrafted mice showed that the contribution from NOX2 KO HSCs was severely compromised in all lineages and developmental stages of hematopoiesis examined. Collectively, these results suggest a critical biological role for NOX2 in maintaining the quiescence and long term self-renewal of HSCs. Similar to normal hematopoiesis, we found out that NOX2 is also widely expressed by functionally defined leukemic stem cells in a murine model of myeloid leukemia generated by expressing the oncogenic translocations BCR-ABL and NUP98-HOXA9. To evaluate the role of NOX2 in leukemogenesis, we established the BCR-ABL/NUP98-HOXA9 model using primitive cells derived from either WT or KO. Intriguingly, NOX2 KO leukemic cells generated a much less aggressive disease upon transplantation into primary and subsequently into secondary recipients. Furthermore, leukemic cells in which NOX2 is suppressed displayed aberrant mitotic activity and altered developmental potential marked by loss of quiescence, enhanced entry into cycle and terminal differentiation. To gain mechanistic insight into the observed phenotype, we isolated leukemic stem cells and performed whole genome expression analysis. The data showed that deficiency of NOX2 leads to downregulation of the cell cycle inhibitor CDKN2C (p18) and robust activation of the granulocyte fate determining transcription factor CEBPε. Thus we conclude that loss of NOX2 impacts leukemogenesis through rewiring of the cell cycle machinery and developmental programs in leukemic stem cells. Finally, we found that in CD34+ primary human AML cells, NOX2 and the other subunits of the complex are abundantly expressed. Furthermore, pharmacologic inhibition of NOX2 with VAS2870, a selective NADPH oxidase inhibitor, reduced the level of ROS and limited the in vitro proliferation and survival of leukemic cells. Next we genetically suppressed the expression of NOX2 in primary human AML cells using sh-RNAs and transplanted these cells into immune compromised mice. Consistent with the murine leukemia, NOX2 knocked down AML cells failed to engraft and expand in vivo. Taken together, our results firmly establish a hitherto unrecognized, prominent regulatory role for NOX2 in the biology of normal and malignant hematopoietic stem cells and imply a potential therapeutic opportunity that can get exploited to treat AML. Disclosures Pollyea: Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member; Alexion: Other: advisory board.

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