Abstract

T cell acute lymphoblastic leukemia/lymphoma (T-ALL/L) is characterized by clonal expansion of immature T lymphocytes that demonstrate extensive proliferation and tissue infiltration. RAS proto-oncogenes are mutated in ∼10% of human T-ALL/Ls, and elevated levels of active Ras•GTP have been obsereved in 50% of these cancers, suggesting that Ras signaling is deregulatd by multiple genetic mechanisims (

Clin. Cancer Res.
6
,
1804
,
2000
). We are performing retroviral insertional mutagenesis in Mx1-Cre, KrasG12D mutant mice, that have a myeloproliferative disorder (
PNAS
101
,
597
,
2004
) to identify genes that cooperate in vivo with hyperactive Ras in the genesis of hematologic malignancies. Unexpectedly, we observe a high incidence of T-ALL/L that is both transplantable and immunphenotypically resembles T-ALL/Ls found in human patients. We have cloned retroviral integration sites from 25 tumors to identify genetic lesions that cooperate with KrasG12D in lymphomagenesis and have identified IKZF1 and AHI1 as common insertion sites in 26% and 15% of tumors, repectively. IKZF1 encodes a zinc finger transcription factor that is required for murine lymphocyte development and is deregulated in human T-ALL/L and AHI1 encodes a scaffolding protein previously implicated in both murine and human leukemias. Furthermore, these T-ALL/Ls frequently aquire mutations in the NOTCH1 gene that are independent of retroviral integration. Interestingly, KrasG12D T-ALL/Ls have variable activation of the MAP Kinase pathway. We have screened cell lines generated from these T-ALL/Ls for sensitivity to γ-secretase and MEK inhibitors and found that biochemical activation predicts drug sensitivity and results in a therapeutic index. We are using multiparameter flow cytometry in conjunction with proliferation assays to idenitfy additional biochemical targets important for tumor proliferation and survival. Our studies, which are in agreement with studies of human T-ALL/L, implicate hyperactive Ras in T cell tumorigenesis and provides a platform for identifying novel cooperating genes and for testing novel therapeutic strategies.

Author notes

Disclosure: No relevant conflicts of interest to declare.