scholarly journals The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

Oncogene ◽  
2012 ◽  
Vol 32 (7) ◽  
pp. 930-938 ◽  
Author(s):  
J Shi ◽  
E Wang ◽  
J Zuber ◽  
A Rappaport ◽  
M Taylor ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Self Renewal ◽  
Polycomb Complex ◽  
Acute Myeloid

scholarly journals A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Matthew E. Massett ◽  
Laura Monaghan ◽  
Shaun Patterson ◽  
Niamh Mannion ◽  
Roderick P. Bunschoten ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Activity ◽  
Leukemia Cell ◽  
Gene Signature ◽  
Pathological Feature ◽  
Self Renewal ◽  
Stem Cell Activity ◽  
Molecular Mechanism Of Action ◽  
Acute Myeloid

AbstractEpigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

scholarly journals RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia

Cell Reports ◽  
2021 ◽  
Vol 36 (7) ◽  
pp. 109559
Author(s):  
Rui Sun ◽  
Lixiazi He ◽  
Hyeyoon Lee ◽  
Andrey Glinka ◽  
Carolin Andresen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bmp Signaling ◽  
Self Renewal ◽  
Acute Myeloid

scholarly journals An Advanced Preclinical Mouse Model for Acute Myeloid Leukemia Using Patients' Cells of Various Genetic Subgroups and In Vivo Bioluminescence Imaging

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120925 ◽  
Author(s):  
Binje Vick ◽  
Maja Rothenberg ◽  
Nadine Sandhöfer ◽  
Michela Carlet ◽  
Cornelia Finkenzeller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Bioluminescence Imaging ◽  
In Vivo Bioluminescence Imaging ◽  
Acute Myeloid

scholarly journals microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia

2010 ◽  
Vol 207 (3) ◽  
pp. 475-489 ◽  
Author(s):  
Yoon-Chi Han ◽  
Christopher Y. Park ◽  
Govind Bhagat ◽  
Jinping Zhang ◽  
Yulei Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ectopic Expression ◽  
Hematopoietic Progenitors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Myeloid Development ◽  
Acute Myeloid ◽  
Myeloid Progenitors

The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR-29a initiates AML by converting myeloid progenitors into self-renewing LSC.

scholarly journals High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
François Hermetet ◽  
Rony Mshaik ◽  
John Simonet ◽  
Patrick Callier ◽  
Laurent Delva ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Cell Surface ◽  
High Fat Diet ◽  
Myeloid Leukemia ◽  
Potent Inhibitor ◽  
Hematopoietic Cells ◽  
High Fat ◽  
Stat3 Signaling ◽  
Acute Myeloid

Abstract Using a MLL-AF9 knock-in mouse model, we discovered that consumption of a high-fat diet (HFD) accelerates the risk of developing acute myeloid leukemia (AML). This regimen increases the clusterization of FLT3 within lipid rafts on the cell surface of primitive hematopoietic cells, which overactivates this receptor as well as the downstream JAK/STAT signaling known to enhance the transformation of MLL-AF9 knock-in cells. Treatment of mice on a HFD with Quizartinib, a potent inhibitor of FLT3 phosphorylation, inhibits the JAK3/STAT3, signaling and finally antagonizes the accelerated development of AML that occurred following the HFD regimen. We can therefore conclude that, on a mouse model of AML, a HFD enforces the FLT3 signaling pathway on primitive hematopoietic cells and, in turn, improves the oncogenic transformation of MLL-AF9 knock-in cells and the leukemia initiation.

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