Scientists Identify New Way to Treat Aggressive Leukemia Subtype, ALL

New approach may combine with existing medications to improve survival.

Mysteries regarding the aggressive nature of a high-risk leukemia subtype called acute lymphoblastic leukemia (ALL) have been dispelled as scientists now understand how a common mutation within the subtype drives the cancer’s aggressiveness.

Additionally, the scientists have identified drugs that may work with existing precision medicines to improve survival.

The study, led by St. Jude Children’s Research Hospital, centered on IKZF1, also known and IKAROS, a gene that is mutated in up to 80% of patients with ALL subtype BCR-ABL1. The subtype can also be referred to as Philadelphia chromosome (Ph-positive) ALL. The result of the mutation is an abnormal protein that drives cancer cell proliferation.

Ph-positive ALL accounts for about 5% of childhood ALL, which is the most common pediatric cancer. The subtype becomes more common with age with 30% of adolescents and young adults infected with the subtype and an even higher percentage of older patients.

While targeted therapies called tyrosine kinase inhibitors (TKIs) increase the likelihood of survival in many patients with the BCR-ABL1 rearrangement, the prognosis remains poor for Ph-positive ALL patients who also have IKZF1 mutations.

For the first time, researchers revealed that IKZF1 mutations cause certain white blood cells with the BCR-ABL1 fusion gene to behave like stem cells. This also affect disease development and treatment, the study reports.

“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, MD, MBBS, member of the St. Jude Department of Pathology. “The insight also led us to a promising new treatment strategy.”

BCR-ABL1 is common in chronic myeloid leukemia (CML). TKIs have helped with extending 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, PhD, a St. Jude staff scientist.

Churchman was successful in developing the first mouse models of IKZF1-mutated 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, researchers revealed that the addition of IKZF1 alterations in combination with Arf mutations was a central event to ALL rather than CML. In pre-B cells with BCR-ABL1, IKZF1 alterations resulted in a pattern of gene expression that resembled blood stem cells and induced an increased production of adhesion molecules that cells use to stick together.

The mutated cells then moved into bone marrow niches to protect themselves from chemotherapy radiation. Expression of the gene for the protein focal adhesion kinase (FAK) also increased. This expression is associated with tumor growth and has resulted in the development of FAK inhibitors.

By screening 483 compounds, scientists were able to determine that a family of retinoid drugs can reverse the stem cell features of these mutant cells and blocked cluster formation. Researchers identified the cancer drug bexarotene and 4 other compounds known as nuclear hormone receptor effectors as potent inhibitors of cell aggregation. The drugs have either been approved by the FDA or are currently in clinical trials.

The drugs were associated with the ability of the TKI dasatinib to kill human cancer cells in the laboratory. The combination therapies also extended the lives of mice with IKZF1-mutated Ph-positive ALL, compared with mice who were treated with dasatinib alone. Research continues to show how to incorporate retinoids or FAK inhibitors into existing treatment of the 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.