scholarly journals Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

2011 ◽  
Vol 194 (1) ◽  
pp. i4-i4
Author(s):  
Alejandro Gutierrez ◽  
Ruta Grebliunaite ◽  
Hui Feng ◽  
Elena Kozakewich ◽  
Shizhen Zhu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Zebrafish Model ◽  
Myc Oncogene ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

2011 ◽  
Vol 208 (8) ◽  
pp. 1595-1603 ◽  
Author(s):  
Alejandro Gutierrez ◽  
Ruta Grebliunaite ◽  
Hui Feng ◽  
Elena Kozakewich ◽  
Shizhen Zhu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Akt Pathway ◽  
Mrna Levels ◽  
Zebrafish Model ◽  
Myc Oncogene ◽  
Pathway Activation ◽  
Cell Acute Lymphoblastic Leukemia

The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN–PI3K–AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.

A Tamoxifen-Dependent Conditional Model of MYC-Induced T Cell Acute Lymphoblastic Leukemia in the Zebrafish.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2808-2808
Author(s):  
Alejandro Gutierrez ◽  
Hui Feng ◽  
Prochownik Edward ◽  
John Kanki ◽  
A. Thomas Look
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Small Molecule ◽  
Lymphoblastic Leukemia ◽  
Fluorescent Microscopy ◽  
Novel Genes ◽  
Zebrafish Model ◽  
Conditional Model ◽  
Human T Cell ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The MYC oncogene plays a central role in the pathogenesis of human T cell acute lymphoblastic leukemia (T-ALL), and our laboratory has previously developed a zebrafish model of Myc-induced T-ALL. The primary strength of the zebrafish as a model system for human disease lies in is its suitability for unbiased forward genetic and small molecule screens. Our central hypothesis is that forward screens performed using our zebrafish model of MYC-induced T-ALL will lead to the identification of entirely novel genes and pathways that play critical roles in MYC-induced leukemogenesis. However, zebrafish from our original line develop rapidly progressive T-ALL prior to achieving reproductive maturity, making this line poorly suited for the performance of large-scale screens. Therefore, a conditional model was required. We have now generated a transgenic zebrafish line that expresses a human MYC-estrogen receptor fusion construct under the control of the zebrafish recombination activating gene 2 (Rag2) promoter, which is lymphocyte-specific. When mated against fish transgenic for a Rag2-GFP transgene, the development and progression of T-ALL can be readily tracked in live fish by fluorescent microscopy. Upon treatment with 4-hydroxytamoxifen (4HT), zebrafish from this line develop fully penetrant T-ALL, with a mean time to tumor onset of 8 weeks. Additionally, removal from 4HT invariably led to complete morphologic remission in leukemic zebrafish from this line, and all of these fish remained alive and were able to mate successfully for greater than 6 months after removal from 4HT. This conditional zebrafish model of MYC-induced T-ALL will now allow the successful performance of forward genetic and small molecule screens to identify known and novel genes and pathways that play critical roles in T-ALL leukemogenesis and MYC-induced transformation. Figure Figure

scholarly journals The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia

Blood ◽  
2017 ◽  
Vol 129 (9) ◽  
pp. 1124-1133 ◽  
Author(s):  
Marta Sanchez-Martin ◽  
Adolfo Ferrando
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Myc Oncogene ◽  
Regulatory Circuit ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a highly proliferative hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation in T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers promoting cell anabolism and cell cycle progression. Oncogenic NOTCH signaling, which is activated in more than 65% of T-ALL patients by activating mutations in the NOTCH1 gene, has emerged as a major regulator of leukemia cell growth and metabolism. T-ALL NOTCH1 mutations result in ligand-independent and sustained NOTCH1-receptor signaling, which translates into activation of a broad transcriptional program dominated by upregulation of genes involved in anabolic pathways. Among these, the MYC oncogene plays a major role in NOTCH1-induced transformation. As result, the oncogenic activity of NOTCH1 in T-ALL is strictly dependent on MYC upregulation, which makes the NOTCH1-MYC regulatory circuit an attractive therapeutic target for the treatment of T-ALL.

scholarly journals Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Kehan Li ◽  
Cunte Chen ◽  
Rili Gao ◽  
Xibao Yu ◽  
Youxue Huang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Growth Retardation ◽  
Lymphoblastic Leukemia ◽  
Downstream Target ◽  
B Cell Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Aggressive Subtype

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of leukemia with poor prognosis, and biomarkers and novel therapeutic targets are urgently needed for this disease. Our previous studies have found that inhibition of the B-cell leukemia/lymphoma 11B (BCL11B) gene could significantly promote the apoptosis and growth retardation of T-ALL cells, but the molecular mechanism underlying this effect remains unclear. This study intends to investigate genes downstream of BCL11B and further explore its function in T-ALL cells. We found that PTK7 was a potential downstream target of BCL11B in T-ALL. Compared with the healthy individuals (HIs), PTK7 was overexpressed in T-ALL cells, and BCL11B expression was positively correlated with PTK7 expression. Importantly, BCL11B knockdown reduced PTK7 expression in T-ALL cells. Similar to the effects of BCL11B silencing, downregulation of PTK7 inhibited cell proliferation and induced apoptosis in Molt-4 cells via up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p27. Altogether, our studies suggest that PTK7 is a potential downstream target of BCL11B, and downregulation of PTK7 expression via inhibition of the BCL11B pathway induces growth retardation and apoptosis in T-ALL cells.

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