Molecular pathogenesis of AML (mouse models of acute myeloid leukemia with AML1-ETO fusion proteins)

2002 ◽  
Vol 76 (S1) ◽  
pp. 249-249 ◽  
Author(s):  
Dong-Er Zhang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Models ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Molecular Pathogenesis ◽  
Acute Myeloid

scholarly journals Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia

2017 ◽  
Vol 1 (20) ◽  
pp. 1682-1693 ◽  
Author(s):  
Ikuko Nakamae ◽  
Jun-ya Kato ◽  
Takashi Yokoyama ◽  
Hidenori Ito ◽  
Noriko Yoneda-Kato
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Models ◽  
Myeloid Leukemia ◽  
Expression Ratio ◽  
Human Patient ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
Protein Levels ◽  
Acute Myeloid ◽  
Myeloid Progenitors

Abstract C/EBPα is a key transcription factor regulating myeloid differentiation and leukemogenesis. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPα for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). Here we show that myeloid leukemia factor 1 (MLF1) stabilizes C/EBPα protein levels by inhibiting the ligase activity of the Trib1-COP1 complex. MLF1 directly interacts with COP1 in the nucleus and interferes with the formation of the Trib1-COP1 complex, thereby blocking its ability to polyubiquitinate C/EBPα for degradation. MLF1 overexpression suppressed the Trib1-induced growth advantage in a murine bone marrow (BM) culture and Trib1-induced AML development in BM-transplanted mouse models. MLF1 was expressed in hematopoietic stem cells and myeloid progenitors (common myeloid progenitors and granulocyte-macrophage progenitors) in normal hematopoiesis, which is consistent with the distribution of C/EBPα. An MLF1 deficiency conferred a more immature phenotype on Trib1-induced AML development. A higher expression ratio of Trib1 to MLF1 was a key determinant for AML development in mouse models, which was also confirmed in human patient samples with acute leukemia. These results indicate that MLF1 is a positive regulator that is critical for C/EBPα stability in the early phases of hematopoiesis and leukemogenesis.

scholarly journals NMR-Based Metabolomic Analysis of the Molecular Pathogenesis of Therapy-Related Myelodysplasia/Acute Myeloid Leukemia

2011 ◽  
Vol 10 (6) ◽  
pp. 2873-2881 ◽  
Author(s):  
Kristin E. Cano ◽  
Liang Li ◽  
Smita Bhatia ◽  
Ravi Bhatia ◽  
Stephen J. Forman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Pathogenesis ◽  
Metabolomic Analysis ◽  
Acute Myeloid

scholarly journals Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells

Blood ◽  
2014 ◽  
Vol 123 (15) ◽  
pp. 2343-2354 ◽  
Author(s):  
Saar Gill ◽  
Sarah K. Tasian ◽  
Marco Ruella ◽  
Olga Shestova ◽  
Yong Li ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Mouse Models ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Antigen Receptor ◽  
Key Points ◽  
Human Acute Myeloid Leukemia ◽  
Engineered T Cells ◽  
Acute Myeloid

Key Points Targeting of CD123 via CAR-engineered T cells results in rejection of human AML and myeloablation in mouse models.

The molecular pathogenesis of acute myeloid leukemia

2005 ◽  
Vol 56 (2) ◽  
pp. 195-221 ◽  
Author(s):  
Björn Steffen ◽  
Carsten Müller-Tidow ◽  
Joachim Schwäble ◽  
Wolfgang E. Berdel ◽  
Hubert Serve
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Pathogenesis ◽  
Acute Myeloid

Hypomethylation of Tumor Suppressor Genes in Acute Myeloid Leukemia: Characteristic of Cell Lines with MLL Abnormalities?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 365-365
Author(s):  
Hilmar Quentmeier ◽  
Sonja Röhrs ◽  
Wilhelm G Dirks ◽  
Claus Meyer ◽  
Rolf Marschalek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Acute Leukemia ◽  
Cell Lines ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Hoxa Cluster ◽  
Acute Myeloid

Abstract Abstract 365 Background: Translocations of the Mixed Lineage Leukemia (MLL) gene occur in a subset (5%) of acute myeloid leukemia (AML) and in mixed phenotype acute leukemia in infancy, a disease with extremely poor prognosis. Animal model systems show that MLL gain of function mutations may contribute to leukemogenesis. Wild-type MLL carries histone methyltransferase activity and affects specific target genes, such us HOXA cluster genes. While the more than three dozen MLL fusion proteins known today exert different specific functions, they finally induce transcription of individual target genes. Consequently, acute lymphoblastic leukemias (ALL) with MLL mutations (MLLmu) exhibit typical gene expression profiles including high-level expression of HOXA cluster genes. Aim of this study was to find a correlation between the MLL mutational status and tumor suppressor gene methylation/expression in acute leukemia cell lines. Results: Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification assay), methylation of 24 different TSG was analyzed in 28 MLLmu and MLLwt acute leukemia cell lines. 1.8/24 TSG were methylated in MLLmu AML cells, 6.2/24 TSG were methylated in MLLwt AML cells. Hypomethylation and expression of the tumor suppressor genes (TSG) BEX2, IGSF4 and TIMP3 turned out to be characteristic of MLLmu acute myeloid leukemia (AML) cell lines. MLL wild-type (MLLwt) AML cell lines displayed hypermethylated TSG promoters resulting in transcriptional silencing. Demethylating agents and inhibitors of histone deacetylases restored expression of BEX2, IGSF4 and TIMP3 confirming epigenetic silencing of these genes in MLLwt cells. The positive correlation between MLL translocation, TSG hypomethylation and expression suggested that MLL fusion proteins were responsible for dysregulation of TSG expression in MLLmu cells. This concept was supported by our observation that Bex2 mRNA levels in MLL-ENL transgenic mouse cell lines required expression of the MLL fusion gene. Conclusion: These results suggest that the conspicuous expression of the TSG BEX2, IGSF4 and TIMP3 in MLLmu AML cell lines is the consequence of altered epigenetic properties of MLL fusion proteins. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells

Oncotarget ◽  
2017 ◽  
Vol 8 (7) ◽  
pp. 11284-11301 ◽  
Author(s):  
Laia Pascual Ponce ◽  
Nadja C. Fenn ◽  
Nadine Moritz ◽  
Christina Krupka ◽  
Jan-Hendrik Kozik ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

scholarly journals Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair

2003 ◽  
Vol 112 (11) ◽  
pp. 1751-1761 ◽  
Author(s):  
Myriam Alcalay ◽  
Natalia Meani ◽  
Vania Gelmetti ◽  
Anna Fantozzi ◽  
Marta Fagioli ◽  
...  
Keyword(s):  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Stem Cell Maintenance ◽  
Cell Maintenance ◽  
Acute Myeloid

A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models

2021 ◽  
Vol 13 (613) ◽  
Author(s):  
Xufen Yu ◽  
Dongxu Li ◽  
Jithesh Kottur ◽  
Yudao Shen ◽  
Huen Suk Kim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Models ◽  
Myeloid Leukemia ◽  
Acute Myeloid
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