Recurrent chromosomal rearrangements implicate oncogenes contributing to T‐cell lymphomagenesis in Lck‐MyrAkt2 transgenic mice

Timakhov, Roman A.; Tan, Yinfei; Rao, Mamta; Liu, Zemin; Altomare, Deborah A.; Pei, Jianming; Wiest, David L.; Фаворова, О. О.; Knepper, Janice E.; Testa, Joseph R.

doi:10.1002/gcc.20683

Cited by 16 publications

(26 citation statements)

References 39 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…21 The MyrAkt2 Tg model was selected because the most frequently observed mutations in T-ALL (ie, Notch activation or PTEN loss) activate AKT. 11,22 Non-Tg mice did not develop disease during the time of the study; however, MyrAkt2;Rpl22 ϩ/ϩ mice developed thymic lymphoma with a median latency of 19 weeks (Figure 2A).…”

Section: Rpl22 Haploinsufficiency Accelerates the Development Of T Lymentioning

confidence: 99%

Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B

Rao

Lee

Gutiérrez

et al. 2012

Blood

Self Cite

135

160

View full text Add to dashboard Cite

Ribosomal protein (RP) mutations in diseases such as 5q؊ syndrome both disrupt hematopoiesis and increase the risk of developing hematologic malignancy. However, the mechanism by which RP mutations increase cancer risk has remained an important unanswered question. We show here that monoallelic, germline inactivation of the ribosomal protein L22 (Rpl22) predisposes T-lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in ϳ 10% of human T-acute lymphoblastic leukemias. Moreover, monoallelic loss of Rpl22 accelerates development of thymic lymphoma in both a mouse model of T-cell malignancy and in acute transformation assays in vitro. We show that Rpl22 inactivation enhances transformation potential through induction of the stemness factor, Lin28B. Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk. (Blood. 2012;120(18):3764-3773) IntroductionIn addition to their role as structural components of ribosomes, ribosomal proteins (RPs) are increasingly understood to play critical roles in development and disease, in some cases from outside of the ribosome. These include roles in regulation of cell-cycle progression, apoptosis, 1 and translation, through direct interactions with mRNA. 2 Mutations in RPs cause diseases collectively termed ribosomopathies, which include myelodysplastic syndromes (MDS) and diamond blackfan anemia (DBA). DBA is caused by mutations in a variety of RPs, with approximately one-half of all cases resulting from mutations in RPS19, RPS26, RPL5, and RPL11, whereas a type of myelodysplastic syndrome known as 5qϪ syndrome has been attributed to the monoallelic loss of RPS14. 3,4 RPS14 haploinsufficiency in 5qϪ syndrome, as well as the ribosome dysfunction observed in other bone marrow failure syndromes, is associated with increased risk in patients for the development of hematologic malignancies. 5 Observations in animal models have similarly linked RP gene mutations with alterations in cancer risk because loss of one copy of numerous, essential RP genes increased susceptibility to tumor formation in zebrafish, 6 suggesting that some RPs may serve as haploinsufficient tumor suppressors. Nevertheless, neither the basis by which RP function as tumor suppressors nor the way RP mutations predispose to malignancy has been explained.The ribosomal protein L22 (Rpl22) is an RNA-binding component of the 60S ribosomal subunit that is not thought to be required for global cap-dependent translation, but its normal physiologic role is poorly understood. We have determined that despite the ubiquitous expression of Rpl22, its germline ablation in mouse is not lethal, unlike ablation of most RP genes. 7,8 Instead, mice in which the Rpl22 gene is biallelically inactivated in the germline are viable, fertile, and grossly normal, with the only striking defect being an exquisitely specific block in the development ...

show abstract

Section: Rpl22 Haploinsufficiency Accelerates the Development Of T Lymentioning

confidence: 99%

Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B

Rao

Lee

Gutiérrez

et al. 2012

Blood

Self Cite

135

160

View full text Add to dashboard Cite

show abstract

“…The Lck-MyrAkt2 transgenic mice develop spontaneous, aggressive thymic lymphomas within 10–20 wks (7-9), with the added advantage that the mutant transgene bypasses the need for activation of phosphoinositides 3,4,5-trisphosphate (PIP 3 ) and PIP 2 generated by PI3K and, thus, cannot be inhibited by Pten. The Lck-MyrAkt2 model exhibits recurrent chromosomal rearrangements that result in overexpression of c-Myc, which is frequently observed in human lymphomas and postulated to cooperate with activated Akt to drive tumor formation (10, 11). …”

Section: Introductionmentioning

confidence: 99%

GSK690693 Delays Tumor Onset and Progression in Genetically Defined Mouse Models Expressing Activated Akt

Altomare

Zhang

Deng

et al. 2010

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Akt plays a central role in regulating tumor cell survival and cell cycle progression and is regarded as a promising therapeutic target. We used genetically defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693.Experimental Design: We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten +/− knockout mice that exhibit endometrial tumors, and TgMI-SIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify downregulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phosphospecific antibodies.Results: GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed downregulation of the Akt pathway, increased apoptosis, and primarily decreased cell proliferation.Conclusion: These results suggest that GSK690693 or other Akt inhibitors might have therapeutic efficacy in human cancers with hyperactivated Akt and/or a dependence on Akt signaling for tumor progression. Clin Cancer Res; 16(2); 486-96.

show abstract

“…Lck-Myr (myristoylated)-Akt2, drives thymic T-cell lymphoma within 12-24 weeks in an Akt dosagedependent manner. 2 In some Lck-Myr-Akt2 founder lines, a recurrent chromosomal inversion implicated the homeobox gene Dlx5 as an oncogene. 3 In subsequent work (manuscript in preparation), we found that transgenic Lck-Dlx5 mice develop spontaneous thymic lymphomas that acquire constitutive activation of Akt, due to loss of Pten expression, as well as up regulation of Myc.…”

Section: Discussionmentioning

confidence: 99%

“…1 In a mouse model of human T-ALL, expression of a constitutively active form of Akt2 specifically in immature T cells is sufficient to drive T-cell lymphoma formation. 2 Tumors from these transgenic mice consistently harbor one or the other of 2 recurrent chromosomal rearrangements that each involve somatic juxtaposition of a T cell receptor (TCR) enhancer and a transcription factor gene, either Dlx5 or Myc -in each case resulting in unregulated expression of Myc protein. 3 Myc is thought to be essential to T cell development, and Myc-null T cells fail to proliferate at the CD4/CD8 double-negative stage in mice.…”

Section: Introductionmentioning

confidence: 99%

Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice

Tan¹,

Sementino

Pei

et al. 2015

Cancer Biology & Therapy

Self Cite

View full text Add to dashboard Cite

Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T-ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (0.5 mM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (0.5 mM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC.

show abstract

Recurrent chromosomal rearrangements implicate oncogenes contributing to T‐cell lymphomagenesis in Lck‐MyrAkt2 transgenic mice

Cited by 16 publications

References 39 publications

Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B

Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B

GSK690693 Delays Tumor Onset and Progression in Genetically Defined Mouse Models Expressing Activated Akt

Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice

Contact Info

Product

Resources

About