Dysregulation of lymphocyte proliferation by chromosomal translocations and sequential genetic changes

Klein, George

doi:10.1002/(sici)1521-1878(200005)22:5<414::aid-bies3>3.0.co;2-5

Cited by 17 publications

(5 citation statements)

References 34 publications

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“…34 There is an interesting parallel between this situation, in which prosurvival bcl-2 augments cmyc transformation, and the situation reported herein for TCL1, in which prosurvival TCL1 is overexpressed in BL cases that contain c-MYC/IgH translocations causing dysregulated expression of the c-MYC proto-oncogene. 35 This parallel suggests a potential synergistic, cell-protective role for increased TCL1 oncoprotein expression in the development of c-MYC-expressing pediatric BL cases.…”

Section: Discussionmentioning

confidence: 95%

TCL1 Expression and Epstein-Barr Virus Status in Pediatric Burkitt Lymphoma

et al. 2005

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Elevated T-cell leukemia-1 (TCL1) oncoprotein expression might promote human Burkitt lymphoma (BL) because increased TCL1 causes Burkitt-like lymphomas in TCL1 transgenic mice. Epstein-Barr virus (EBV) infection has been implicated as a cause of increased TCL1 expression in multiple BL cell lines, suggesting a critical connection between EBV and TCL1-induced BL. The TCL1 expression and EBV status of 14 sporadic pediatric BL cases was determined by immunohistochemical staining for TCL1 and in situ hybridization for EBV-encoded RNA (EBER). Our results showed TCL1 protein in 11 cases, predominantly in the nucleus with strong-intensity staining. EBER was positive in 4 cases, with 3 of these cases also TCL1+. In the 10 cases that were EBER-, TCL1 was strongly positive in 8. These data indicate that the TCL1 oncoprotein is expressed strongly in most pediatric BL cases. However, persistent EBV is not essential for increased TCL1 expression, although elevated TCL1 and c-MYC coexpression might cooperate in the development of most pediatric and adult BL cases.

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Section: Discussionmentioning

confidence: 95%

TCL1 Expression and Epstein-Barr Virus Status in Pediatric Burkitt Lymphoma

et al. 2005

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“…One approach to defining the genetic alterations required for leukemogenesis has been physical mapping of recurring chromosomal rearrangements associated with particular hematologic malignancies (Rowley, 2000). Chromosomal analyses coupled with advances in cytogenetic methodology have generated a wealth of information regarding the gross genomic alterations associated with leukemic transformation (Drexler et al, 1995;Veldman et al, 1997;Klein, 2000). These alterations include chromosomal translocations, inversions, duplications, and deletions.…”

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confidence: 99%

Bcl-xL and Akt cooperate to promote leukemogenesis in vivo

et al. 2003

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To analyse individual factors that may contribute to leukemic transformation in vivo, we have developed a murine model of leukemogenesis based on the early hematopoietic precursor cell FL5.12. FL5.12 cells are interleukin-3 (IL-3) dependent for growth, proliferation, and survival. Relative resistance to cell death following IL-3 withdrawal can be conferred by either overexpression of the Bcl-x L apoptotic inhibitor, or constitutive activation of the serine/threonine kinase Akt. The ability of Bcl-x L or a constitutively active myristylated Akt to promote leukemic transformation of FL5.12 cells was compared in athymic nu + /nu + mice. Bcl-x L alone could not promote leukemic transformation, but mice injected with FL5.12 cells overexpressing Bcl-x L and a dominant-negative p53 construct developed leukocytosis and blastic infiltration of lymph nodes, spleen, and liver with features of a highgrade lymphoid malignancy. In contrast to the cells injected into these animals, cell lines derived from the mice were able to proliferate in the absence of IL-3, and were found to have constitutively activated Akt. This constitutive activation was associated with a variety of alterations of the signaling pathway regulating Akt activity, including alterations of PTEN mRNA and protein expression. In addition, some of these leukemic clones demonstrated concurrent constitutive upregulation of ERK activity. A constitutively active Akt construct introduced into FL5.12 cells promoted similar clonal expansion in vivo, with emergence of clonal IL-3-independent proliferation. Bclx L and Akt appeared to function cooperatively in this model, enhancing rapid clonal outgrowth in vivo relative to Akt alone. These results implicate activated Akt and growth-factor independence in leukemogenic transformation, and demonstrate the potential for in vivo analysis of genetic determinants of leukemogenesis.

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“…It is present less frequently (15-20%) in sporadic cases worldwide (1). The hallmark of BL is the juxtaposition of the c-myc gene to the Ig heavy-or light-chain gene by chromosomal translocation, which results in the constitutive expression of c-myc (2). The contribution of EBV to BL genesis is still controversial.…”

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confidence: 99%