Loss of CDKN2C accelerates progression of Notch-1 induced T lymphoblastic leukemia via activation of LMO2

Abstract

The cyclin-dependent kinases inhibitor CDKN2C (p18INK4C, p18) is a member of the INK4 family that specifically blocks the activity of CDK4/6 in the G1 phase of cell cycle. In the hematopoietic system, deletion of p18 is associated with T cell malignancies in mice and B cell malignancies in humans. The mice reconstituted with p18 knockout (ko) bone marrow (BM) cells spontaneously developed acute T lymphoblastic leukemia (T-ALL) in serial transplantation (2 years after transplantation) originating from a CD3low cell population. However, how p18 is involved in the development of T-ALL leukemia is largely unknown. In this study, Intercellular domain of Notch1 (ICN-1) induced T-ALL model was used to explore the role of p18 deficiency in the development of T-ALL leukemia. Both hematopoietic stem and progenitor LSK (Lin− c-Kit+ Sca-1+) cells transduced with ICN1-GFP retrovirus from p18 +/+ or p18 −/− mice initiated the T-ALL. The majority of CD3+ cells were CD4/8 double positive in p18 +/+ group while that of CD3+ cells were CD4/8 double negative in p18 −/− group. The serial transplantation of T-ALL cells showed accelerated progression of leukemia in p18 −/− group compared with the p18 +/+ group in first, secondary and tertiary transplantation ( P =0.01, P P p18 −/− group compared with p18 +/+ group. The gene expression analysis also showed higher expression of Lmo2 and N-myc in the leukemia cells of p18 −/− group compared with p18 +/+ group. Deletion of p18 activates the expression of Lmo2 and N-myc although a mechanism is yet to be further defined. Taken together, our current study provides evidence and mechanism insights for the role of p18 deficiency during progression of T-ALL.