Germline Genetic Variation in IKZF1 and Predisposition to Childhood ALL Interview with:

Michelle Churchman, PhD Scientific Manager of Charles Mullighan's laboratory Department of Pathology St Jude Children's Research Hospital

Dr. Michelle Churchman

Michelle Churchman, PhD
Scientific Manager of Charles Mullighan’s laboratory
Department of Pathology
St Jude Children’s Research Hospital What is the background for this study? What are the main findings?

Response: The role of IKZF1 alterations in the development of B-progenitor acute lymphoblastic leukemia (B-ALL) and their role in determining poor outcome of treatment has been a long-term focus of our groups. We had previously identified somatic (tumor-acquired) IKZF1 deletions and mutations in high-risk leukemia, and identified several mechanisms by which these mutations drive high-risk leukemia. We also have a long-standing interest in studying inherited genetic risk factors of childhood ALL. In this latest study, our research team identified a family in Germany with a history of B-cell deficiency and B-ALL that had a germline IKZF1 mutation, prompting us to investigate whether inherited IKZF1 variants are related to predisposition to ALL in general. To investigate this, the IKZF1 gene was sequenced from the germline DNA of nearly 5000 patients enrolled on St. Jude Children’s Research Hospital and Children’s Oncology Group front-line ALL trials. We identified 27 unique inherited (germline) IKZF1 variants in 44 patients and found that most of them perturbed the normal functions of the encoded Ikaros transcription factor. Particularly, several of the variants lost the ability to bind DNA and regulate expression of transcriptional targets.

We know from previous studies that genes involved in differentiation and adhesion are overexpressed in IKZF1-altered leukemic cells, which results in abnormal adhesion between cells and components of the bone marrow.

Many of the variants resulted in increased adhesion. We show that several of these germline variants caused leukemic cells to be less sensitive to drugs. What should readers take away from your report?

Response: While it has been well established that somatic IKZF1 alterations are often observed in B-ALL and are important predictors of treatment response and risk of relapse, our studies demonstrate that deleterious IKZF1 variants also exist in our inherited genetic make-up and can predispose to the development of ALL. What recommendations do you have for future research as a result of this study?

Response: Biologically, these variants are very interesting for understanding the regulatory networks that IKZF1 influences. Some of the variants with the most striking effects occur within regions of the protein that have no known function, but clearly they must be important for interactions that have yet to be determined. Clinically, it will be important to identify more patients that harbor rare IKZF1 variants and formally study their outcomes, particularly within various subtypes of B-ALL. Further studies are needed to determine if identification of an IKZF1 variant in a patient can be predictive of ALL risk or response to therapy. Ultimately, the goal is to be able to inform the appropriate course of treatment to prevent relapse. Is there anything else you would like to add?

Response: This was a multi-institutional study involving three research groups at St. Jude Children’s Research Hospital (Drs Nichols, Mullighan and Yang), the Children’s Oncology Group and several investigators in Europe. Thank you for your contribution to the community.

Citation: Abstract presented at the 2016 ASH abstract

Germline Genetic Variation in IKZF1 and Predisposition to Childhood Acute Lymphoblastic Leukemia

Michelle L. Churchman, PhD1*, Maoxiang Qian, Ph.D2, Ranran Zhang, M.D3*, Geertruy Kronnie, PhD4, Wenjian Yang, PhD5*, Hui Zhang, M.D., Ph.D2,3, Tobia Lana6*, Paige Tedrick7*, Rebekah Baskin, PhD7*, Katherine Verbist, PhD8*, Meenakshi Devidas, PhD9, Elizabeth Raetz, MD10, Eric Larsen, MD11*, Paul L. Martin, MD, PhD12, W. Paul Bowman13*, Naomi Winick, MD14, Elaine R Mardis, PhD15*, Robert S. Fulton, PhD15*, Martin Stanulla, MD16*, William E. Evans, PharmD5, Mary V. Relling, PharmD5, Ching-Hon Pui, MD8, Rupert Handgretinger, MD17, Stephen P. Hunger18*, Mignon L. Loh, MD19, Kim E. Nichols, MD20*, Charles Mullighan, MBBS, MSc, MD21 and Jun J. Yang, PhD5

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Last Updated on December 10, 2016 by Marie Benz MD FAAD

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