Mechanisms of treatment-free remission in a mouse model of chronic myeloid leukemia

PROJECT SUMMARY/ABSTRACT Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm diagnosed in about 5,000 Americans each year, characterized by the presence of the t(9;22) Philadelphia chromosome and its protein product, the BCR-ABL1 tyrosine kinase, in the leukemic cells. Current therapy for CML is centered on tyrosine kinase

inhibitors (TKIs) such as imatinib mesylate, which can induce cytogenetic and molecular remissions in most patients, who then enjoy normal age-adjusted life expectancy. This clinical success will lead to an estimated prevalence of ~200,000 CML patients in the U.S. by the year 2050, with attendant drug costs of >$10 billion that

can include burdensome out-of-pocket payments for patients. In addition, TKIs can have substantial side effects, some of which are potentially life-threatening. Accordingly, recent efforts have been made to stop TKI therapy in CML patients who have achieved molecular remission. About half of such patients experience progressive

molecular relapse following TKI stopping, but the other half either remain molecularly undetectable or experience low-level recurrence that does not progress (collectively termed treatment-free remission or TFR), suggesting that there are biological mechanisms that limit the ability of small numbers of leukemic stem cells to expand and

cause disease. These mechanisms are not understood, and represent a major unmet need in current CML research, as we do not have validated approaches to increase the proportion of CML patients who are eligible to stop their TKI nor to increase the proportion of patients who can maintain TFR. This application seeks to address these unmet needs by exploiting a newly developed CML mouse model

of TFR. In this model, hematopoietic stem cells (HSCs) from an existing conditional double transgenic (dTg) mouse model of CML are transplanted into recipient congenic B6 mice without the use of conditioning radiation. The resulting bone marrow (BM) chimeras contain clones of dTg HSC in a background of normal BM,

representing a physiological model of early CML. Mice bearing large (>10%) clones of dTg HSC uniformly develop CML-like leukemia when BCR-ABL1 expression is induced, but mice with smaller (