The BMP pathway: A unique tool to decode the origin and progression of leukemia.

The microenvironment (niche) governs the fate of stem cells (SCs) by balancing self-renewal and differentiation. Increasing evidence indicates that the tumor niche plays an active role in cancer, but its important properties for tumor initiation progression and resistance remain to be identified. Clinical data show that leukemic stem cell (LSC) survival is responsible for disease persistence and drug resistance, probably due to their sustained interactions with the tumor niche. Bone morphogenetic protein (BMP) signaling is a key pathway controlling stem cells and their niche. BMP2 and BMP4 are important in both the normal and the cancer context. Several studies have revealed profound alterations of the BMP signaling in cancer SCs, with major deregulations of the BMP receptors and their downstream signaling elements. This was illustrated in the hematopoietic system by pioneer studies in chronic myelogenous leukemia that may now be expanded to acute myeloid leukemia and lymphoid leukemia, as reviewed here. At diagnosis, cells from the leukemic microenvironment are the major providers of soluble BMPs. Conversely, LSCs display altered receptors and downstream BMP signaling elements accompanied by altered functional responses to BMPs. These studies reveal the role of BMPs in tumor initiation, in addition to their known effects in later stages of transformation and progression. They also reveal the importance of BMPs in fueling cell transformation and expansion by overamplifying a natural SC response. This mechanism may explain the survival of LSCs independently of the initial oncogenic event and therefore may be involved in resistance processes.