Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell (HSC) malignancy that is induced upon the balanced translocation of chromosomes 9 and 22 and the resulting formation of a Philadelphia (Ph) chromosome. The product of the Ph chromosome is the BCR-ABL tyrosine kinase. The constitutively active tyrosine kinase activity of BCR-ABL is the crux of the malignancy and causes defective integrin signaling and adhesion in HSCs. Recent studies in our laboratory indicate an abnormal and increased dependency on selectins and their ligands for homing and engraftment of these leukemic stem cells within the bone marrow (BM) niche. The main objectives of this proposal are to 1) investigate and further define the nature of the adhesive molecules that contribute to engraftment of malignant stem cells in CML patients and 2) develop methods that will block engraftment of CML stem cells without affecting the engraftment of normal stem cells. To induce CML in donor stem cells we will employ our BCR-ABL transduction/transplantation model system. To delineate the critical adhesion molecules that mediate malignant stem cell engraftment compound donor and/or recipient mutant mice will express genetic mutations for adhesion molecules expressed in HSCs or BM endothelium, respectively. These BM transplantation studies will collectively determine the critical adhesion factors for engraftment of leukemic stem cells. Neuraminidase, anti-selectin reagents, monoclonal antibodies and small molecule selectin antagonists will be tested for their efficacy to block CML stem cell engraftment first in a murine model for CML and then using xenografts of human CML stem cells transplanted into NOD/SCID/yc-deficient mice. The observations from these studies will engender novel clinically applicable methods for blocking CML stem cell engraftment in autographed patients.
Taken together, these studies will support the NIH mission by contributing to a deeper understanding of the cause of homing and engraftment of leukemic stem cells in CML patients. The development of clinically relevant methods for blocking the engraftment of CML stem cells will improve current techniques of treating CML patients, thereby leading to better management of the disease as well as an increase in patient longevity.
|Krause, Daniela S; Lazarides, Katherine; Lewis, Juliana B et al. (2014) Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood 123:1361-71|