Retinoids may increase effectiveness of targeted therapies against high-risk leukemia

Researchers have discovered how a common mutation in a high-risk leukemia subtype drives the cancer’s aggressiveness and have identified drugs that may work with existing precision medicines to improve survival. St. Jude Children’s Research Hospital scientists led the study, which was published online today in the journal Cancer Cell.

The research focused on IKZF1, also known as IKAROS, a gene that is mutated in up to 80 percent of patients with the high-risk acute lymphoblastic leukemia (ALL) subtype BCR-ABL1. This subtype is also known as Philadelphia chromosome (Ph-positive) ALL, named for the chromosomal rearrangement that creates the BCR-ABL1 fusion gene, which results in an abnormal protein that drives cancer cell proliferation.

Ph-positive ALL accounts for about 5 percent of childhood ALL, which is the most common pediatric cancer. The subtype becomes more common with age and accounts for up to 30 percent of adolescents and young adults with ALL and an even higher percentage of older patients. While targeted therapies called tyrosine kinase inhibitors (TKIs) have transformed the outlook for many cancer patients with the BCR-ABL1 rearrangement, the prognosis remains poor for Ph-positive ALL patients who also have IKZF1 mutations.

In this study, investigators showed for the first time that IKZF1 mutations cause certain white blood cells with the BCR-ABL1 fusion gene to behave like stem cells. Researchers also reported how that affects disease development and treatment.

“The research shows why, in this era of targeted therapies, Ph-positive ALL patients who also have IKZF1 mutations fare so poorly,” said corresponding author Charles Mullighan, M.D., M.B.B.S., member of the St. Jude Department of Pathology. “The insight also led us to a promising new treatment strategy.”

BCR-ABL1 is a hallmark of chronic myeloid leukemia (CML). TKIs have dramatically extended the lives of patients with CML, which is a slowly progressing, almost exclusively adult disease that almost always involves the BCR-ABL1 fusion. “We started this study in part to understand why IKZF1 mutations were selectively associated with ALL, not CML,” said first author Michelle Churchman, Ph.D., a St. Jude staff scientist.

Churchman developed the first mouse models of Ikzf1-muated Ph-positive ALL with and without mutations in the Arf gene. Arf encodes a tumor suppressor protein and is altered in about half of Ph-positive ALL.

Using the mouse models, investigators showed that the addition of Ikzf1 alterations, particularly in combination with Arf mutations, was a central event in driving ALL rather than CML. In pre-B cells with BCR-ABL1, IKZF1 alterations induced a pattern of gene expression characteristic of blood stem cells and resulted in increased production of adhesion molecules that cells use to stick together. Cells with the mutation clustered together and invaded bone marrow niches that may protect them from chemotherapy. Expression of the gene for the protein focal adhesion kinase (FAK) also increased. Such over-expression occurs in many tumors and has resulted in the development of FAK inhibitors.

Researchers conducted a screen of 483 compounds and found that a family of retinoid drugs reversed the stem cell features of these mutant cells and blocked cluster formation. Researchers identified the cancer drug bexarotene and four other compounds known as nuclear hormone receptor effectors as potent inhibitors of cell aggregation. The drugs have been approved for use by the U.S. Food and Drug Administration or are currently in clinical trials. Investigators found evidence the drugs worked in part by binding to and inducing expression of the normal IKZF1 gene. The compounds also worked in other ways to reverse the stem-cell features, halt cell proliferation and promote differentiation of altered cells.

The drugs, as well as experimental agents known as FAK inhibitors, enhanced the ability of the TKI dasatinib to kill human cancer cells in the laboratory. The combinations also extended the lives of mice with Ikzf1-mutated Ph-positive ALL, compared to mice treated with dasatinib alone. Research continues into how to incorporate retinoids or FAK inhibitors into existing treatment of this high-risk leukemia.

“The findings highlight the potential of drugs that promote differentiation and work synergistically with existing therapies to save lives and improve outcomes for these high-risk patients,” Mullighan said.

Overall long-term survival rates for St. Jude ALL patients are now about 94 percent, and cancer-free survival is about 86 percent. But long-term, cancer-free survival is about 75 percent for young Ph-positive ALL patients without IKZF1 mutations and about 55 percent for those with the alterations, according to a recent study.