leukemia stem cell
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Blood ◽  
2021 ◽  
Author(s):  
Tina M. Schnoeder ◽  
Adrian Schwarzer ◽  
Ashok Kumar Jayavelu ◽  
Chen-Jen Hsu ◽  
Joanna Kirkpatrick ◽  
...  

In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a de-regulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lianjun Zhang ◽  
Le Xuan Truong Nguyen ◽  
Ying-Chieh Chen ◽  
Dijiong Wu ◽  
Guerry J. Cook ◽  
...  

AbstractAcute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.


Author(s):  
Linus Angenendt ◽  
Marius Wöste ◽  
Jan-Henrik Mikesch ◽  
Maria Francisca Arteaga ◽  
Adrian Angenendt ◽  
...  

We have recently identified the G protein-coupled neuropeptide receptor Calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event free survival (EFS) (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P=0.0001), overall survival (OS) (HR, 1.55; 95% [CI], 1.06-2.27; P=0.025) and cumulative incidence of relapse (CIR) (HR, 2.10; 95% CI, 1.49-1.96; P<0.0001) when adjusting for age, white blood cell count and genetic risk. Despite its association with leukemia stem cell (LSC) signatures, CALCRL expression remained associated with all endpoints when compared to the LSC17 score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating drug-tolerant AML cells in humans.


2021 ◽  
Vol 13 (612) ◽  
Author(s):  
Jingfeng Zhou ◽  
Shubo Wang ◽  
Danian Nie ◽  
Peilong Lai ◽  
Yiqing Li ◽  
...  

2021 ◽  
pp. 106673
Author(s):  
Adriana Plesa ◽  
Christophe Roumier ◽  
Joris Gutrin ◽  
Marie-Virginie Larcher ◽  
Marie Balsat ◽  
...  

2021 ◽  
Vol 50 ◽  
pp. 102117
Author(s):  
Nikolaos Spyrou ◽  
Eirini P. Papapetrou

Cell Reports ◽  
2021 ◽  
Vol 34 (4) ◽  
pp. 108670
Author(s):  
Qingfei Jiang ◽  
Jane Isquith ◽  
Luisa Ladel ◽  
Adam Mark ◽  
Frida Holm ◽  
...  

2020 ◽  
Vol 99 ◽  
pp. 106477
Author(s):  
Breann Yanagisawa ◽  
Brandy Perkins ◽  
Theodoros Karantanos ◽  
Mark Levis ◽  
Gabriel Ghiaur ◽  
...  

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