Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) was the first malignancy associated with a specific chromosomal anomaly termed the Philadelphia Chromosome. The anomaly was shown to cause the fusion of two genes to produce the BCR-ABL oncogene, which drives the disease. Bcr-Abl induces CML by driving aberrant differentiation of hematopoietic stem cells. This occurs specifically because Bcr-Abl expression causes elevated expression of another oncoprotein, c-Myc.

CML patients in the early stages of the disease, known as chronic phase are usually responsive to drugs known as tyrosine kinase inhibitors (TKIs) that target Bcr-Abl, in that the 5-year progression-free survival rate is 68%. However, long-term remission is achieved less than half the time, with a large percentage of patients experiencing relapse upon cessation of TKI treatment. This has been interpreted as indicating that a population of leukemia initiating cells (LICs) is refractory to TKI treatment. LICs are thought to possess properties similar to hematopoietic stem cells such as self-renewal and quiescence, rendering them resistant to most therapies. Therefore, CML LICs serve as a reservoir of BCR-ABL possessing but TKI-resistant cells that prevent cure. Patients must remain on TKI drugs indefinitely, which has a number of deleterious implications. Xtem Pharmaceuticals is developing technology aimed at both killing CML LICs and sensitizing them to other treatments, such as TKI drugs. Our goal is to help CML patients achieve permanent remission without continuous therapy.