scholarly journals Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

2016 ◽  
Vol 12 (4) ◽  
pp. 2746-2751 ◽  
Author(s):  
Zheng Ge ◽  
Min Li ◽  
Gang Zhao ◽  
Lichan Xiao ◽  
Yan Gu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Dynamin 2

Heterozygous Mutation Of Dynamin 2 Expands The Pool Of IL-7 Responsive Leukemic Stem Cells In T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 613-613
Author(s):  
David J. Curtis ◽  
Fiona C. Brown ◽  
Michael Collett ◽  
Sarah E. Lucas ◽  
Jesslyn Saw ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Leukemic Stem Cells ◽  
Gtpase Domain ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Dynamin 2

Abstract Early thymocyte progenitor T-cell acute lymphoblastic leukemia (ETP-ALL) is a poor prognosis malignancy that has a distinct genetic basis characterized by activating mutations of the IL-7 signaling pathway. Recurrent mutations spanning Dynamin 2 (Dnm2), a gene encoding a large GTPase required for clathrin-mediated endocytosis, have been identified in ETP-ALL although why these mutations are enriched in ETP-ALL remains obscure. We have utilized the Lmo2 transgenic mouse model to define the role of DNM2 mutations in ETP-ALL. Sequencing of 11 cases of Lmo2-derived T-ALL identified two novel Dnm2 mutations, a frameshift (Serine126fs) and a premature stop (Isoleucine135stop) mutation within the GTPase domain, which confirmed the relevance of this mouse model for studying Dnm2 mutations. We mated Lmo2 mice with mice carrying a germ-line missense mutation of Dnm2 in the GTPase domain (V235G), which impairs GTPase activity. This Dnm2 mutation had two important biologic effects on Lmo2-derived T-ALL: an increased penetrance (90% compared with 50% by 12 months of age; p<0.05) and a more immature phenotype (DN1-3 compared with ISP8). To address the mechanism of these effects, we examined the phenotype and expression profile of early leukemic stem cells harboring the Dnm2 mutation. The major abnormality was an expansion of IL-7 responsive leukemic stem cells with increased proliferation and survival. Intriguingly, the presence of Dnm2 mutations sensitized leukemic cells to killing by a small molecule inhibitor of Dnm2. Together, our data provide the first experimental evidence that Dnm2 mutations are enriched in ETP-ALL by expanding the pool of IL-7 responsive leukemic stem cells. Furthermore, our data supports further testing of Dynamin inhibitors in this subset of poor prognosis T-ALL. Disclosures: No relevant conflicts of interest to declare.

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.

Rare occurrence of a STAT5B N642H mutation in adult T-cell acute lymphoblastic leukemia

2015 ◽  
Vol 208 (1-2) ◽  
pp. 52-53 ◽  
Author(s):  
Xiaolin Ma ◽  
Lijun Wen ◽  
Lili Wu ◽  
Qingrong Wang ◽  
Hong Yao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Rare Occurrence ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

2021 ◽  
Vol 22 (3) ◽  
pp. 1388
Author(s):  
Natalia Maćkowska ◽  
Monika Drobna-Śledzińska ◽  
Michał Witt ◽  
Małgorzata Dawidowska
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Epigenetic Modification ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Global Methylation ◽  
Current State ◽  
History Of ◽  
Cell Acute Lymphoblastic Leukemia

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

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