PROJECT SUMMARY

Despite decades of research, MDS remains largely resistant to therapy. Recent genome sequencing projects in MDS have identified various genetic mutations. However, thus far, few of these mutations have been responsive to therapies. Furthermore, therapies that target specific mutations have been limited by the appearance of new mutations in subpopulations of MDS cells that are resistant to the therapy. These limitations in current available treatments have prompted us to search for alternative targets that may be more stable and will not be constantly mutating. Therefore, we focused on cells that are present in the surrounding microenvironment of MDS cells in the bone marrow (stromal cells). Our observations as well as observations from other laboratories indicate that cells from the MDS bone marrow microenvironment send signals that contribute to the development of MDS or to its transformation to acute myeloid leukemia (AML). To identify these signals we compared expression of all genes between cells of the MDS bone marrow microenvironment isolated from MDS patients, cells of the same patients that developed AML and cells of the healthy bone marrow microenvironment isolated from healthy people. Our comparison indicated that MDS cells disrupt communication signals between bone marrow stromal cells to establish new communications with them. Such signals render bone marrow stromal cells from MDS patients metabolically hyperactive so as to make a large amount of proteins. These proteins are transferred to the MDS cells and contribute to their transformation to AML. We also identified changes in the expression of specific genes that regulate mRNA stability as important signals driving transformation of MDS to AML. We also sequenced the genome of bone marrow microenvironment cells isolated from patients with MDS as well as their cells when they later developed AML and currently analyzing these data aiming to identify mutations in stromal cells of the bone marrow microenvironment that are associated with the development of MDS and with transformation of MDS to AML. Lastly, we used a “humanized” mouse in which we have engineered human bone and implanted MDS cells from patients and found that MDS cells compromised bone formation and several bone marrow functions. We are now using these humanized mice to reproduce the abnormal gene expression and the identified mutations and examine their contribution to MDS. We expect that this work will allow us to identify new signals contribute to induction of MDS and transformation to AML. Interrupting these signals with drugs may be a way to create a hostile MDS environment and a new approach to treat the disease.