Wednesday, May 8, 2024
5/8/2024
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 (<2%) dTg clones do not develop CML, but instead exhibit fluctuating low levels of dTg granulocytes in peripheral blood that mimics TFR. The proposed project will test whether two distinct processes, oncogene-induced replicative stress and the BM microenvironment/niche, are involved in the ability of the host to control the malignancy. Aim 1 will test whether oncogene-induced replicative stress is involved by a incorporating loss-of-function mutation in the p19Arf gene in the dTg donor cells. Aim 2 will test whether elements of the BM niche, including immune cells and cytokines, are required for disease control. Aim 3 will translate these findings to human CML BM samples using the spatial mass cytometry to define the topography of the CML niche and correlate this with TFR outcomes. These results will yield important new knowledge about the pathophysiology of TFR that should motivate novel therapeutic approaches to increase the frequency and durability of TFR in CML patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
