scholarly journals PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (23) ◽  
pp. 3609-3617 ◽  
Author(s):  
Jinjun Dang ◽  
Lei Wei ◽  
Jeroen de Ridder ◽  
Xiaoping Su ◽  
Alistair G. Rust ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Genetic Alteration ◽  
Human Leukemia ◽  
Key Points ◽  
Leukemia Development ◽  
Common Target ◽  
Mouse Mutagenesis

Key Points Heterozygous alterations of Pax5, the most common target of genetic alteration in ALL, promote ALL in mouse mutagenesis models. Leukemia development is accompanied by the acquisition of genetic alterations commonly observed in human leukemia.

scholarly journals Genetic loss of SH2B3 in acute lymphoblastic leukemia

Blood ◽  
2013 ◽  
Vol 122 (14) ◽  
pp. 2425-2432 ◽  
Author(s):  
Arianne Perez-Garcia ◽  
Alberto Ambesi-Impiombato ◽  
Michael Hadler ◽  
Isaura Rigo ◽  
Charles A. LeDuc ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Suppressor Gene ◽  
Key Points

Key Points SH2B3 is a recessive tumor suppressor gene with germline and somatic mutations in ALL.

scholarly journals Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2180-2186 ◽  
Author(s):  
JM Cayuela ◽  
A Madani ◽  
L Sanhes ◽  
MH Stern ◽  
F Sigaux
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Lymphoblastic Leukemia ◽  
Genetic Defect ◽  
Suppressor Gene ◽  
Genetic Alteration ◽  
Multiple Tumor ◽  
Cell Acute Lymphoblastic Leukemia

No constant genetic alteration has yet been unravelled in T-cell acute lymphoblastic leukemia (T-ALL), and, to date, the most frequent alteration, the SIL-TAL1 deletion, is found in approximately 20% of cases. Recently, two genes have been identified, the multiple tumor- suppressor gene 1 (MTS1) and multiple tumor-suppressor gene 2 (MTS2), whose products inhibit cell cycle progression. A characterization of the MTS locus organization allowed to determine the incidence of MTS1 and MTS2 inactivation in T-ALL. MTS1 and MTS2 configurations were determined by Southern blotting using 8 probes in 59 patients with T- ALL (40 children and 19 adults). Biallelic MTS1 inactivation by deletions and/or rearrangements was observed in 45 cases (76%). Monoallelic alterations were found in 6 cases (10%). The second MTS1 allele was studied in the 4 cases with available material. A point mutation was found in 2 cases. The lack of MTS1 mRNA expression was observed by Northern blot analysis in a third case. A normal single- strand conformation polymorphism pattern of MTS1 exons 1alpha and 2 was found and MTS1 RNA was detected in the fourth case, but a rearrangement occurring 5′ to MTS1 exon 1 alpha deleting MTS1 exon 1Beta was documented. One case presented a complex rearrangement. Germline configuration for MTS1 and MTS2 was found in only 7 cases. The localization of the 17 breakpoints occurring in the MTS locus were determined. Ten of them (59%) are clustered in a 6-kb region located 5 kb downstream to the newly identified MTS1 exon 1Beta. No rearrangement disrupting MTS2 was detected and more rearrangements spared MTS2 than MTS1 (P<.01). MTS1 but not MTS2 RNA was detected by Northern blotting in the human thymus. These data strongly suggest that MTS1 is the functional target of rearrangements in T-ALL. MTS1 inactivation, observed in at least 80% of T-ALL, is the most consistent genetic defect found in this disease to date.

scholarly journals The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Joni Van der Meulen ◽  
Viraj Sanghvi ◽  
Konstantinos Mavrakis ◽  
Kaat Durinck ◽  
Fang Fang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Specific Tumor ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Gender Specific

Key Points The H3K27me3 demethylase UTX is recurrently mutated in male T-ALL and escapes X-inactivation in female T-ALL blasts and normal T cells. The loss of Utx contributes to T-ALL formation in vivo and UTX inactivation confers sensitivity to H3K27me3 inhibition.

PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events

Blood ◽  
2014 ◽  
Vol 124 (4) ◽  
pp. 567-578 ◽  
Author(s):  
Rui D. Mendes ◽  
Leonor M. Sarmento ◽  
Kirsten Canté-Barrett ◽  
Linda Zuurbier ◽  
Jessica G. C. A. M. Buijs-Gladdines ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Human T Cell ◽  
Key Points ◽  
Inactivation Mechanism ◽  
Cell Acute Lymphoblastic Leukemia

Key Points Microdeletions represent an additional inactivation mechanism for PTEN in human T-cell acute lymphoblastic leukemia. PTEN microdeletions are RAG-mediated aberrations.

scholarly journals Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia

Cancer Cell ◽  
2012 ◽  
Vol 22 (2) ◽  
pp. 153-166 ◽  
Author(s):  
Kathryn G. Roberts ◽  
Ryan D. Morin ◽  
Jinghui Zhang ◽  
Martin Hirst ◽  
Yongjun Zhao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Cytokine Receptor ◽  
Receptor Signaling

scholarly journals Exploring the Role of a Novel Tumor Suppressor - OSR2 in T-ALL

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-26
Author(s):  
Arpan A. Sinha ◽  
Pilar I. Andrade ◽  
Megan Malone-Perez ◽  
Syed T Ahmed ◽  
J. Kimble Frazer
Keyword(s):  
Transcription Factor ◽  
Tumor Suppressor ◽  
Childhood Cancer ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Expression Patterns ◽  
Tumor Biology ◽  
Transgenic Animals ◽  
Genetic Alterations ◽  
Allelic Loss

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, representing &gt;25% of all cancers in children 0-14 years. Despite major advancements in pediatric ALL treatment, it remains the second most lethal childhood cancer, accounting for ~25% of deaths. The two types of ALL are precursor-B, or B-ALL, and precursor-T, or T-ALL, which have distinct molecular landscapes. Of these types, T-ALL comprises about 15% and 25% of pediatric and adult cases, respectively, and is historically considered more aggressive and treatment-resistant, with an inferior prognosis. In the precision medicine era, it is imperative to identify genetic alterations and aberrant gene expression patterns, to better understand tumor biology and improve treatment outcomes by identifying new therapeutic targets. Our study investigates a novel transcription factor, odd-skipped related transcription factor 2 (OSR2), which we hypothesize is a putative T-ALL tumor suppressor. We are using a zebrafish T-ALL model expressing transgenic human MYC (hMYC) regulated by a lymphoblast-specific promoter, rag2. Prior work in zebrafish and human T-ALL found low OSR2 levels in ~95% of T-ALL. Based on this, we then used RNA-seq to analyze 10 hMYC zebrafish T-ALL, confirming low-to-absent osr2 in all 10 T-ALL relative to wild-type (WT) T cells. We further confirmed decreased osr2 expression by qRT-PCR of additional T-ALL and WT thymocytes. We hypothesized that if OSR2 suppresses T-ALL, impaired zebrafish Osr2 function might increase T-ALL incidence and shorten latency. To test this, we bred osr2-mutant fish to rag2:hMYC transgenic animals to create three genotypes: heterozygous osr2-mutant (osr2het) fish, heterozygous hMYC (hMYChet) fish, and compound-heterozygote (osr2het;hMYChet) fish. We screened these genotypes for T-ALL incidence by serial fluorescence microscopy, with T-ALL subsequently confirmed by fluorescence-based flow cytometry. By 7 months of age, we found 9/18 (50%) of double-heterozygous fish developed T-ALL, compared to 0/7 hMYChet fish (p = 0.026); osr2het fish also did not develop T-ALL. Together, our findings suggest osr2 allelic loss accelerates MYC-driven T-ALL, supporting our hypothesis that osr2 is a T-ALL tumor suppressor. Disclosures No relevant conflicts of interest to declare.

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