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Improving therapy for CRLF2-rearranged Ph-like acute lymphoblastic leukemia

Charles Mullighan

Dr Charles Mullighan, St Jude Children’s Research Hospital (Memphis, US).
Funding period: 2019 – 2022.

This research project is kindly supported through the Estate of Florence Brown.

Acute lymphoblastic leukemia (ALL) remains a leading cause of childhood cancer death, and one type of this disease, Philadelphia-like ALL (Ph-like ALL), has an extremely poor outcome.

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 the continual expression of a protein called ABL1 which has been shown to stimulate leukemia cell growth.

Ph-like ALL cells have a variety of genetic changes that activate various genes resulting in cancer 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 are not very effective in CRLF2-rearranged ALL, so new treatments are urgently required.

This project will use two new approaches to develop therapies that are effective in CRLF2-rearranged ALL.

The first new approach is using proteolysis-targeting chimeras (PROTACs). PROTACs have emerged as a highly promising approach which uses the cells own machinery to destroy abnormal proteins in cancer cells. 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.

CRISPR/Cas9 genome-wide screening has proven very useful in other cancer and leukemia settings, and may identify vulnerabilities or “Achilles heels” that can be targeted for the treatment of CRLF2-rearranged ALL.