Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets

Abstract

We compared the gene expression pattern of thymic tumors from precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) that arose in transgenic mice that overexpressed SCL, LMO1 or NUP98-HOXD13 (NHD13) with that of thymocytes from normal littermates. Only two genes, Ccl8 and Mrpl38, were consistently more than fourfold overexpressed in pre-T LBL from all three genotypes analyzed, and a single gene, Prss16 was consistently underexpressed. However, we identified a number of genes, such as Cfl1, Tcra, Tcrb, Pbx3, Eif4a, Eif4b and Cox8b that were over or under-expressed in pre-T LBL that arose in specific transgenic lines. Similar to the situation seen with human pre-T LBL, the SCL/LMO1 leukemias displayed an expression profile consistent with mature, late cortical thymocytes, whereas the NHD13 leukemias displayed an expression profile more consistent with immature thymocytes. We evaluated two of the most differentially regulated genes as potential therapeutic targets. Cfl1 was specifically overexpressed in SCL-LMO1 tumors; inactivation of Cfl1 using okadaic acid resulted in suppression of leukemic cell growth. Overexpression of Ccl8 was a consistent finding in all three transgenic lines, and an antagonist for the Ccl8 receptor-induced death of leukemic cell lines, suggesting a novel therapeutic approach.

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…PBX3 has been observed to be aberrantly overexpressed in a variety of tumours [54][55][56][57][58] ; however, little is known about its biological roles in tumorigenesis and progression. Our current study demonstrates that PBX3 plays determinant roles in HCC TIC properties, in particularly, controlling directly the expression of TIC surface markers a2d1 and EpCAM, stem cell master genes SOX2 and SALL2, as well as regulating the self-renewal and tumorigenicity potential.…”

T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome

“…The absence of SIL-TAL in this series of T-LBL is therefore notable, although SIL-TAL has been described in pediatric T-LBL (34). Microarray analyses of murine transgenic lymphomas induced by oncogenes such as SCL/TAL1 and LMO1 may only be instructive for subcategories of human T-LBL because, as we show here, these transcripts are only present in a minority of cases (44). The SCL/TAL1 transgenic model may indeed be most instructive for TCRD del -LBL, but our data also agree with the involvement of a distinct basic helix-loophelix transcriptional regulator.…”

Mitochondrial ribosomes in cancer

“…Gene expression profiling of mouse precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) identified MRPL38 gene expression as an oncogenic pathway indicator and a prognostic marker [122]. MRPL38 was one of the two genes found to be overexpressed more than four-fold in thymic tumors from clinically-sick transgenic mice generated by overexpression of SCL, LMO1 or NHD13, three known pre-T LBL genes [122].…”

“…MRPL38 was one of the two genes found to be overexpressed more than four-fold in thymic tumors from clinically-sick transgenic mice generated by overexpression of SCL, LMO1 or NHD13, three known pre-T LBL genes [122]. The relevance of mL38 to cancer prognosis was also highlighted in another study aiming to explore the alterations of mitochondrial protein abundance in ovarian cancer, by comparing the mitochondrial proteomics profile of a pair of human ovarian carcinoma cell lines (SKOV3/SKOV3.ip1) with different metastatic potentials [123].…”