Prevention of relapse in juvenile myelomonocytic leukemia (JMML) by inhibition of immune checkpoint CD47

Juvenile myelomoncytic leukemia (JMML) is a rare, but highly aggressive childhood leukemia caused by overproliferation of the granulocytic and monocytic lineages. The only curative treatment is allogeneic hematopoietic cell transplantation (allo-HCT). However, relapse risk is up to 50%, especially in PTPN11 mutated subtype. Our preliminary data indicated that JMML cell express various immune checkpoints and regulatory molecules that may mediate immune escape. One of these is CD47, a don’t eat me signal preventing phagocytosis. Our goal is to understand the impact of CD47 on JMML relapse after HSCT and to prevent relapse by targeting CD47 in PTPN11-knockin mice. Using flow cytometry analysis, we will characterize CD47 expression in different leukemic cell types. To address whether CD47 is directly upregulated by mutated PTPN11, we will interfere with downstream signaling using PI3K and MEK inhibitors. We will establish phagocytosis assay and use anti-CD47 inhibitor to identify the role of CD47 in JMML. We expect that inhibition of CD47 will result in increased phagocytosis of JMML cells and reduced relapse risk. Therefore, our studies will pave the way for future magrolimab trials.

Publication History

Article published online:
17 May 2022