LIM Domain Only-2 (LMO2) Induces T-Cell Leukemia by Two Distinct Pathways

Smith, Stephen B.; Tripathi, Rati; Goodings, Charnise; Cleveland, Susan M.; Mathias, Elizabeth; Hardaway, J. Andrew; Elliott, Natalina E.; Yi, Yajun; Chen, Xi; Downing, James R.; Mullighan, Charles G.; Swing, Deborah A.; Tessarollo, Lino; Li, Liqi; Love, Paul E.; Jenkins, Nancy A.; Copeland, Neal G.; Thompson, Mary Ann; Du, Yang; Davé, Utpal P.

doi:10.1371/journal.pone.0085883

Cited by 52 publications

(70 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3E), consistent with a microenvironment supportive of tumor growth. Similar epithelial-free regions containing DCs, vasculature, and fibroblast networks were observed in thymic lymphomas from LMO2 transgenic mice, which overexpress an oncogene frequently upregulated in human T-ALL (25) (Fig. 3 D and E).…”

Section: That Sirpαsupporting

confidence: 65%

“…Exon sequencing revealed that many LN3 tumors have activating Notch1 mutations, and some LMO2 tumors are also NOTCH-driven (25). Thus, DCs and IGF1R signaling can promote survival of NOTCH-driven murine T-ALL cells.…”

Section: Discussionmentioning

confidence: 99%

“…C57BL/6J and CD11c-EYFP [B6.Cg-Tg(Itgax-EYFP)1Mnz/J] mice were purchased from The Jackson Laboratory. LN3 and LMO2 (B6.CD2-Lmo2) (25) mice were euthanized upon lymphoma detection, as identified by enlarged lymph nodes, hunched posture, reduced motility, ruffled fur, and/or labored breathing. All mice were housed under specific pathogen-free conditions at The University of Texas at Austin (UT Austin) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NICHD/NIH).…”

Section: Methodsmentioning

confidence: 99%

“…CEL files were kindly provided by Charles Mullighan from cases at St. Jude Children's Research Hospital, Memphis, TN, and have been previously described (GEO accession no. GSE33315) (25,33). Microarray data were normalized using the Robust MultiChip Averaging (RMA) algorithm (58), as implemented in the Bioconductor package Affy.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

Triplett

Cardenas

Lancaster

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.

show abstract

Section: That Sirpαsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

Triplett

Cardenas

Lancaster

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…19,20 In support of this hypothesis, several reports have shown a striking correlation between LMO2, TAL1, and Olig2 based on gene expression analysis in human and murine T-cell leukemia. [21][22][23] In future studies, it will be interesting to explore whether LMO2 interacts with Olig2 to regulate GSCs and brain tumorigenesis. Presence of tumor-derived vascular components sheds light on the plasticity of cancer cells and the potential involvement of cancer stem cells in cancer-associated angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

Kim

Hitomi

et al. 2015

Cell Death Differ

View full text Add to dashboard Cite

Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.

show abstract

Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

Almeida,

T'Sas,

Pagliaro

et al. 2024

HemaSphere

View full text Add to dashboard Cite

T‐lineage acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological malignancy that accounts for 10%–15% of pediatric and 25% of adult ALL cases. Although the prognosis of T‐ALL has improved over time, the outcome of T‐ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T‐ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto‐oncogene MYB is highly expressed in diverse hematologic malignancies, including T‐ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T‐ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event‐free survival of pediatric T‐ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB‐driven T‐ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T‐cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T‐ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T‐ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T‐ALL.

show abstract

LIM Domain Only-2 (LMO2) Induces T-Cell Leukemia by Two Distinct Pathways

Cited by 52 publications

References 53 publications

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

Contact Info

Product

Resources

About