Inca1, also known as inhibitor of cyclin-dependent kinase interacting with cyclin A1, is a key regulator in cell cycle control. It functions as a CDK inhibitor, negatively regulating the kinase activity of cyclin-cyclin-dependent kinase complexes, especially those involving cyclin A1 and CDK2. Inca1 is associated with pathways related to cell proliferation, apoptosis, and chromatin remodeling [2,3]. Its proper function is crucial for normal cellular growth and preventing uncontrolled cell division, thus having significant biological importance. Genetic models, such as gene knockout mouse models, have been instrumental in studying its function.

In Inca1-deficient mice, several significant phenotypes were observed. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, yet it seemed largely dispensable for normal hematopoiesis. However, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. In leukemia mouse models, AML1-ETO9a-induced proliferation was not sustained in Inca1-deficient cells in vivo. Leukemia induction and maintenance were severely impaired in Inca1-/-bone marrow cells, and the re-initiation of leukemia was also significantly inhibited in the absence of Inca1 in MLL-AF9-and c-myc/BCL2-positive leukemia mouse models [1]. In Inca1(- / -) embryonic fibroblasts, there was an increase in the fraction of S-phase cells, and in Inca1(- / -) mice, there was increased CDK2 activity in the spleen with altered spleen architecture [2].

In conclusion, Inca1 is a crucial regulator of cell proliferation, especially in hematopoietic cells and leukemia-initiating cells. Gene knockout mouse models have revealed its distinct functional properties in normal and cancer-related cells, highlighting its potential as a target for leukemia-specific therapy approaches.