Improving therapy for CRLF2-rearranged Ph-like acute lymphoblastic leukemia
Charles Mullighan
MDSt. Jude Children's Research Hospital
Project Term: July 1, 2019 - June 30, 2022
CRLF2-rearranged ALL is the most common subset of Ph-like ALL, has a very poor prognosis and lacks effective therapy. This project will use two novel approaches to improve treatment. The first is developing proteolysis-targeting chimeras to degrade JAK2 and inhibit constitutive JAK-STAT signaling. In the second approach, we will use CRISPR/Cas9 activating and inhibitory genomic screens to identify cellular dependencies, vulnerabilities and synthetic lethal opportunities for therapy.
Acute lymphoblastic leukemia (ALL) remains a leading cause of childhood cancer death. Our prior studies examining the genetic changes that drive ALL identified a subtype termed “Ph-like” ALL. Leukemia cells in Ph-like ALL have patterns of gene expression similar to another type of ALL harboring an abnormality called the Philadelphia (Ph) chromosome. The Ph chromosome results in expression of BCR-ABL1, an abnormal fusion of two genes that causes constant activity of ABL1, a kinase that fuels leukemia cell proliferation. Ph-like ALL cells have a variety of genetic changes that also activate kinases and abnormal cell growth. One of the most common is a genetic change leading to abnormal expression of a gene named CRLF2. Patients with CRLF2-rearranged ALL have some of the worst outcomes in ALL. Existing drugs to inhibit the JAK-STAT signaling pathway that is activated by CRLF2 show limited activity in CRLF2-rearranged ALL, and new treatments are urgently required. This project will use two new approaches to develop therapeutic approaches in CRLF2-rearranged ALL. The first, proteolysis-targeting chimeras (PROTACs) has emerged as a highly promising approach to redirect a normal cell process to degrade and destroy abnormally active proteins in cancer cells. We have developed a series of PROTAC molecules directed against JAK2 and will test the activity of these in a range of test tube and experimental models of CRLF2-rearranged ALL. Our goal is to develop at least one PROTAC that is potent and specific for JAK2, and may be developed as a therapeutic for patients with CRLF2 ALL. PROTACs will be tested in combination with existing therapies in experimental models of ALL. The second approach will use the recently developed technique of CRISPR/Cas9 genome editing, in which precise cuts or changes to cell DNA can be precisely made. Genome editing may be used to result in gene inactivation or activation, either to single genes or large numbers of genes. Here we will use CRISPR/Cas9 genome-wide screening in human CRLF2-rearranged cell lines in the laboratory, as they grow without drug or in the presence of chemotherapy drugs or kinase inhibitors. This will identify genes that are essential for the growth of CRLF2-rearranged leukemic cells, and also genes and growth pathways that, when inhibited, lead to cell death. This has proven very useful in other cancer and leukemia settings, and may identify hitherto unexpected vulnerabilities or “Achilles heels” for the treatment of CRLF2-rearranged ALL.