With new study, researchers strive to lower risk of ALL recurrence among children

Leukemia accounts for one out of every four cancer cases among children. Survival rates have risen dramatically in the last 50 years, but even so leukemia remains the second leading cause of cancer death among those younger than 20 years old. One particular type, acute lymphoblastic leukemia, is by far the most common form of leukemia (and cancer) found in children, adolescents, and young adults — in the United States, approximately 2,800 children are diagnosed with it every year, and about a fifth of those who experience full remission will see the disease return.

City of Hope scientist Markus Müschen, M.D., Ph.D., the Norman and Sadie Lee Professor in Pediatrics, is determined to improve that prognosis. The Chair of the Department of Systems Biology at City of Hope’s Beckman Research Institute and Associate Director of Basic Science at City of Hope’s Comprehensive Cancer Center, Dr. Müschen has focused his research efforts on combating pediatric acute lymphoblastic leukemia (ALL). In partnership with Shai Izraeli, M.D., a research professor in City of Hope’s Department of Systems Biology and Chair of the Rina Zaizov Pediatric Hematology and Oncology Division at Schneider Children’s Medical Center of Israel, Müschen is striving to drive down the risk of ALL recurrence among kids and young adults.

Müschen and Izraeli’s collaboration is the result of a grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, which was established in 2016 by a gift from the Harvey L. Miller Family Foundation to support the exchange of ideas, strategies, and therapies between City of Hope and Israeli investigators backed by the Israel Cancer Research Fund (ICRF). The Norman and Sadie Lee Foundation provided additional funding for the project.

“This is a marriage between two excellent research groups and a great opportunity to support both the advancement of treatments for children with cancer in Israel and research at City of Hope,” said Izraeli. “These two causes are not only complementary, they’re synergistic. Discoveries made in Israel could have a huge impact on American children with cancer, and the superb science at City of Hope could have a significant impact on treating children with cancer in Israel.”

This is the second Barron Program grant awarded to Izraeli, who in 2016 partnered with Hua Yu, Ph.D., co-leader of the Cancer Immunotherapeutics Program in the Comprehensive Cancer Center at City of Hope, on a study designed to develop new therapeutic approaches for high-risk ALL. The progress they made led not only to Izraeli’s new work with Müschen but also to his permanent appointment to City of Hope in 2018, though he continues to serve as head of the Dotan Research Center for Hematological Malignancies at Tel Aviv University. Bringing Izraeli in-house has accelerated his ALL research and opened new areas of inquiry for both scientists.

Leukemias are blood-cell disorders that arise when the bone marrow produces either immature cells or healthy cells that are then transformed into dysfunctional ones. Typically, it only takes a small number of these irregular stem cells to cause the disease, but they can often be eradicated using targeted therapies that effectively prevent recurrence. B-cell leukemia (B-ALL) describes a specific type of fast-growing cancer that results when the bone marrow manufactures too many dysfunctional lymphocytes, a type of white blood cell. In these cases, the cancer cells have traditionally been difficult to locate, so treatment has been much less successful.

In his research, Izraeli had discovered a novel “reckless driver” of childhood leukemia: mutations in JAK2 that lead to the uncontrolled proliferation of leukemic cells. The leukemias carrying this mutation are a subgroup of very high-risk leukemias in both children and adults. That discovery led to clinical trials in the Children’s Oncology Group that tested whether targeted drug therapies carrying JAK inhibitors could mitigate the leukemias.

Izraeli and Yu used the 2016 Barron funding to complete a detailed genomic study performed by Izraeli’s group in Israel that compared diagnoses to relapsed leukemia samples with the JAK2 abnormality. They discovered a much more complex picture than anticipated: The JAK2 mutation is often replaced by another “reckless” signaling driver called RAS, and the findings suggested that treating the leukemias with only the JAK2 inhibitor, as in the COG trials, would not be sufficient to overcome them.

These observations and later key studies in Dr. Müschen’s lab have led to new discoveries about how JAK2 and RAS signaling drivers interact. Izraeli and Müschen are hopeful that smart, innovative targeting of both the JAK2 and RAS signaling pathways could lead to a cure for these high-risk leukemias.

“The sophisticated models developed in the Müschen laboratory and City of Hope’s infrastructure are hugely appealing,” said Izraeli. “For example, for a recent visit I brought with me the genomic data of an Israeli family that has had many cases of childhood leukemia. I plan to analyze this data with the team at City of Hope, and this may lead to a new discovery of the genetic causes of the disease.”

Howard Hughes Medical Institute faculty scholar, Müschen studied in Düsseldorf and Cologne, Germany, and at the Institut Pasteur in Paris, France. After a postdoctoral fellowship in Chicago he joined the faculty of UC San Francisco, where he served as a full professor with tenure for seven years. In 2016, he joined City of Hope. His research is focused on the development of a methodology for predicting ALL relapse along with a drug-discovery program designed to prevent it. His work explores oncogenic signaling in B cell tumors and mechanisms of drug resistance.

That Izraeli retains his position as head of the largest division of pediatric hematology and oncology in Israel — Schneider Children’s Medical Center treats a large number of children with leukemia every day — helps to facilitate and accelerate their collaborative research into a cure for childhood leukemia. “I’m an active clinician-scientist involved in the clinical care of children with leukemia, as well as many international trials,” said Izraeli. “This is relatively unique — there are few physician-scientists in this field with both clinical and scientific expertise.”

Together, Müschen and Izraeli are pursuing a number of innovative avenues to advance research tied to B-ALL and the abnormal metabolism of leukemic cells. In one new collaborative study, Izraeli is researching how activation of the cytokine receptor IL-7 causes leukemia while Müschen has discovered that the mechanism of this activation leads to abnormal expression of a cell surface molecule that could be targeted by antibodies City of Hope is currently developing.

In another example, Izraeli has for several years been studying the problem of B-ALL growth in the central nervous system, which is a serious clinical problem because chemotherapy and radiation treatments may cause short- or long-term damage to a child’s developing brain. Izraeli’s group has discovered that to survive in the brain environment leukemia cells have to synthesize fatty acids from scratch, and it could be that blocking this synthetic pathway may be used to treat CNS leukemia. Müschen has been interested in precisely the same pathway in B cell lymphoma, and so another unexpected opportunity has arisen from the partnership.

“It’s the synergy of bringing together two creative minds interested in a similar problem,” said Izraeli. “I like this work because it’s translational research in its truest meaning: it starts with a patient-relevant problem. Detailed basic research studies in the lab may lead to discoveries that can then be translated to novel diagnostic or therapeutic approaches for patients. That daily bridge between the labs and patients gives my life meaning.”