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Research Highlights

Michelle Churchman, PhD, and Charles Mullighan, MD, MBBS

Michelle Churchman, PhD, and Charles Mullighan, MD, MBBS 

Two leukemias. One shared genetic alteration. Why are the outcomes so different?

The mystery has been solved about why two types of leukemia that share the same genetic alteration behave so differently and often have quite different outcomes. The discovery—made by St. Jude researchers and published in the journal Cancer Cell—offers a promising new cancer treatment strategy.

BCR-ABL1 is a well-known genetic alteration associated with several different types of leukemia. The alteration is often present in both chronic myeloid leukemia (CML) and a subtype of acute lymphoblastic leukemia (ALL) called IKZF1-mutated BCR-ABL1 ALL. Yet, these cancers behave much differently. CML, a slow-growing cancer that occurs mostly in adults, is often sensitive to targeted therapies called tyrosine kinase inhibitors, or TKIs. These drugs are a precision medicine success story. TKIs have transformed the outlook for patients with CML by targeting the abnormal BCR-ABL1 alteration.

In contrast, IKZF1-mutated BCR-ABL1 ALL is an aggressive disease that occurs in children and adults. TKIs are less effective against this high-risk ALL subtype, and patients are less likely to be cured.

Scientists have discovered how mutations in a gene called IKZF1 or IKAROS drive the development of ALL rather than CML, resulting in an aggressive leukemia that is less responsive to TKIs. In this study, researchers showed that IKZF1 mutations cause certain white blood cells with BCR-ABL1 to retain stem-cell like characteristics. That leads to a more aggressive disease and may help leukemic cells hide from targeted therapies.

“The research shows why, in this era of targeted therapies, patients with IKZF1-mutated BCR-ABL1 ALL fare so poorly,” said Charles Mullighan, MD, MBBS, Pathology. “That insight led us to a promising new treatment strategy that we are pursuing in the laboratory.”

Eighteen genes identified that contribute to brain tumor

St. Jude scientists have identified eight tumor-promoting oncogenes and 10 tumor suppressor genes that converge on a handful of cell functions and help to launch the pediatric brain tumor ependymoma.

The findings dramatically expand understanding of ependymoma, which until now has been linked to alterations in just two genes. The tumor is discovered in 150 to 200 children and adults annually in the U.S., where it is the third most common pediatric brain tumor.

Researchers expect insight from this study will lead to new chemotherapy agents and more effective treatment of a cancer that remains incurable in about 28 percent of pediatric patients.

The study appeared in the scientific journal Nature Genetics.


Discovery yields promising strategy for making tumor cells easier to kill

Richard Kriwacki, PhD (at left), and Ariele Follis, PhD

Richard Kriwacki, PhD (at left), and Ariele Follis, PhD

St. Jude scientists have discovered another way the tumor suppressor protein p53 earns its title as guardian of the genome.

p53 is one of the most famous cancer-related molecules. Its job is to keep tumors from forming. The protein does that by prompting stressed or damaged cells to die or stop dividing. In most cancers, the protein or the pathway that controls p53 does not work properly.

p53 is best known for working in the cell nucleus. But earlier research showed p53 also works outside the nucleus of cells to trigger cell death.  

Scientists have now discovered how p53 achieves the latter task. The results also suggest how small molecules may be used in the future to trigger the same mechanism to help kill cancer cells.

“These results expand our understanding of how p53 regulates cell behavior and highlight a possible new way to make tumor cells easier to kill,” said Richard Kriwacki, PhD, of St. Jude Structural Biology.

The study appeared in the journal Molecular Cell.


Teaching old cells new tricks

Michael Dyer, PhD; Dan Hiler, PhD; and Xiang Chen, PhD

From left) Michael Dyer, PhD; Dan Hiler, PhD; and Xiang Chen, PhD

Hopes for teaching “old” cells new tricks got a boost from research led by St. Jude scientists.

They have developed a new way to make replacement eye cells from adult nerve cells. The process involves coaxing mature cells to return to an immature state. These are the induced pluripotent stem cells that can then be reprogrammed to become different adult cells. One promising use of the cells is to restore vision lost to age-related macular degeneration, retinitis pigmentosa and Stargardt’s disease.

The scientists also found a way to compare the ability of different types of stem cells to create specialized eye cells called retinal cells. Investigators learned that stem cells from certain eye cells produce more vision replacement cells than do certain skin stem cells.

“This research helps to answer an important scientific question by showing that the source of the stem cell makes a difference,” said Michael Dyer, PhD, of St. Jude Developmental Neurobiology and a Howard Hughes Medical Institute investigator. The research was published in the journal Cell Stem Cell. 

Scientists uncover how a common mutation causes brain diseases

Researchers have discovered how the most common genetic cause of two devastating brain disorders disrupts the normal function of nerve cells. The finding suggests a possible new treatment strategy for amyotrophic lateral sclerosis (ALS), which is also called Lou Gehrig disease, and frontotemporal dementia (FTD).

The mutation occurs in a gene named C9ORF72.

Scientists at St. Jude and the University of Massachusetts Medical School found the mutation blocks movement of RNA and other molecules in and out of the cell’s command center or nucleus. That disrupts important cell processes, such as assembling the proteins that do the work of cells.

Investigators checked nerve cells generated from people with the mutation and found that RNA built up in the cell nucleus. That did not happen in nerve cells from people without the mutation. RNA also did not build up in the nucleus of non-nerve cells from patients with the mutation.

ALS and FTD involve the deterioration and death of nerve cells in the brain and spinal cord. That leads to muscle weakness, paralysis plus other symptoms as well as problems walking or swallowing. There are no treatments to halt or reverse the process. Most patients die within five years of diagnosis.

“This study reveals the key defect that we need to reverse in treatment, possibly by knocking out or silencing the mutant gene,” said J. Paul Taylor, MD, PhD, Cell and Molecular Biology chair and a Howard Hughes Medical Institute investigator.

The study appeared in the journal Nature.


Improving diagnosis of chest tumors

Is it cancer or a fungal infection? For children with a mass or lump in their chest cavity, the answer is not always immediately clear.

No single sign or test can reveal which masses are cancerous and which are benign tumors caused by the fungal infection histoplasmosis. For many patients, a diagnosis requires biopsy surgery.

Monika Metzger, MD, and Elisabeth Adderson, MD

Monika Metzger, MD (at left), and Elisabeth Adderson, MD

Research led by St. Jude investigators could lead to a faster and simpler approach.

Scientists found two previously overlooked clues in the health records of 131 children and teens with chest masses. Patients with enlarged lymph nodes in the neck and low levels of certain white blood cells were more likely to have cancer. Masses located in front of the heart were also more likely to be malignant. The results were published in the Journal of Pediatrics.

Researchers now plan to track whether factors discovered in this study will allow faster and more accurate diagnoses without surgery.

“The problem has been that there are both benign and malignant causes of these masses,” said Elisabeth Adderson, MD, of St. Jude Infectious Diseases. “In some parts of the country, particularly in the Ohio and Mississippi River valleys, the masses are more likely to be caused by infection than cancer.”

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