Bcl11a Causes p21^Cip1 Down-Regulation and Transplantable Leukemia in Nf1-Deficient Mice.

Inactivation of the tumor suppressor gene, NF1, is associated with chronic and acute forms of myeloid diseases including juvenile myelomonocytic leukemia. Nf1-deficiency mouse models have shown some phenotypes reminiscent of those of the human disease. However, Nf1mutation in itself does not lead to leukemia. We reported the identification of 37 common proviral insertion sites, loci containing candidate genes whose mutation could cooperate with inactivation of Nf1 to result in BXH-2 AML. Among these candidate genes, Bcl11a, was able to cause leukemia/lymphoma in bone marrow transduction and transplantation assay using Nf1-deficient cells. In this report, we have found that transplantation of these leukemia cells induced secondary leukemia in syngeneic recipient mice. In patients, we previously reported that BCL11A was expressed in juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia samples. Interestingly, high expression levels of BCL11A are also observed in two specific subsets of samples from a large cohort of patients with acute myelogenous leukemia. Moreover, these subsets of patients tended to have a worse outcome. Regarding the biochemical mechanisms underlying the oncogenicity of Bcl11a, we have recently found that p21^Cip1 induction by doxorubicin is severely impaired in Bcl11a-expressing cells, while other cell-cycle regulatory proteins are not affected. Examination of BCL11A’s role in leukemia patients using both over-expression and shRNA knocking-down approaches is underway.