p15Ink4b Functions in determining hematopoietic cell fates: implications for its role as a tumor suppressor

Abstract

The p15Ink4b gene is frequently hypermethylated in myeloid neoplasia and has been demonstrated to be a tumor suppressor. Since it is a member of the INK4b family of cyclin-dependent kinase inhibitors, it was initially presumed that its loss in leukemic blasts caused a dysregulation of the cell cycle. However, animal model experiments over the last several years have produced a very different picture of how p15Ink4b functions in hematopoietic cells and how its loss contributes to myelodysplastic syndrome and myeloid leukemia. It is clear now, that in early hematopoietic progenitors, p15Ink4b functions outside of its canonical role as a cell cycle inhibitor. Its functions are involved in signal transduction and influence the development of erythroid, monocytic and dendritic cells.

Figure 1. Impaired homeostasis of myeloid cells in p15Ink4b-deficient mice

A simplified scheme of hematopoietic stem cells (HSC) differentiating toward myeloid lineages is presented. Increased production (red arrow pointing up) of granulocyte-macrophage progenitors (GMP) and monocytes (Mo), as well as decreased production (black arrow pointing down) of megakaryocyte-erythrocyte progenitors (MEP), common DC progenitors (CDP), and conventional DCs (cDC) in p15Ink4-deficient mice are indicated. Multipotent progenitors (MPP), common myeloid progenitors (CMP), common lymphoid progenitors (CLP), macrophage/dendritic cell progenitors (MDP), monocyte-derived DCs (Mo-DC), macrophages (Mφ), plasmacytoid DCs (pDC).

Figure 2. Silencing of p15Ink4b in myeloid cells affects development of several hematopoietic cell lineages that may cumulatively contribute to AML development

MPN (myeloproliferative neoplasm), CMML (chronic myelomonocytic leukemia), AML (acute myeloid leukemia), cDC (conventional dendritic cells)