Development and characterization of T cell leukemia cell lines established from SCL/LMO1 double transgenic mice

Abstract

We have established a panel of nine immortal cell lines from T cell malignancies which arose in mice transgenic for the SCL and LMO1 genes. Cells from the primary malignancies initially grew very slowly in vitro, loosely attached to a stromal layer, before gaining the ability to proliferate independently. Upon gaining the ability to proliferate in the absence of a stromal layer, these cell lines grew rapidly, doubling every 14-23 h, to a very high density, approaching 10 7 cells/ml. Whereas the tumors which arise in SCL/LMO1 double transgenic mice are typically diploid or pseudodiploid, the cell lines were all grossly aneuploid, suggesting the possibility that additional genetic events were selected for in vitro. Given that SCL and LMO1 gene activation are both commonly seen in human patients with T cell acute lymphoblastic leukemia, these cell lines may be a useful in vitro model for the human disease. Leukemia (2001) 15, 141-147.

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

“…[18][19][20][21][22][23] They suggest that the initiating event occurs in T cells in the thymus or in the bone marrow. The transformed cells then readily spread to other organs and the PB, and a highly malignant T-cell leukemia evolves rapidly.…”

Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma

“…Mice were killed when signs of illness developed. 16,17 The treatment protocol was approved by the Animal Use Committee at both Roswell Park Cancer Institute and the National Cancer Institute.…”

“…To investigate the timing of Notch1 mutations in SCL/LMO1 mice, we examined thymocytes from clinically healthy SCL/LMO1 mice aged 4 to 12 weeks. We previously demonstrated [16][17][18] that thymocytes from 4-to 5-week-old SCL/LMO1 mice had decreased total thymocytes, an increased proportion of CD4 Ϫ CD8 Ϫ cells, an increased apoptotic index, and oligoclonal Tcrb gene rearrangements. Despite oligoclonal Tcrb gene rearrangements, suggesting the emergence of one or more clonal populations of thymocytes, these thymocytes are not fully transformed, since they do not form tumors when transplanted into immunodeficient mice.…”

p16INK4A tumor suppressor gene expression and CD3ϵ deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis

“…[16][17][18][19] Thus, the marked increase in the tumor incidence and the reduction of the asymptomatic period observed in more complex transgenic mouse models such as TAL1xMO1 and TAL1xLMO1xp16 INK4Aϩ/Ϫ indicate that several genetic events in addition to TAL1 expression are necessary for leukemogenesis. 17,[20][21][22] CDKN2 inactivation is observed in more than 80% of human T-ALL cases. Analysis of the locus revealed frequent homozygous deletion of exon 2 that leads to the loss of both proteins p16 ink4a and p14 Arf .…”