ASH18: RNA Sequencing Identifies More Subtypes of Childhood Leukemia

MedicalResearch.com Interview with:

Charles G. Mullighan, MBBS (Hons), MSc, MD Member, St. Jude Faculty Co-Leader, Hematological Malignancies Program Medical Director, St. Jude Biorepository William E. Evans Endowed Chair St. Judes Children’s Research Hospital Memphis, TN

Dr. Mullighan

Charles G. Mullighan, MBBS (Hons), MSc, MD
Member, St. Jude Faculty
Co-Leader, Hematological Malignancies Program
Medical Director, St. Jude Biorepository
William E. Evans Endowed Chair
St. Judes Children’s Research Hospital
Memphis, TN

MedicalResearch.com: What is the background for this study?

 

Response: B-lineage acute lymphoblastic leukemia (B-ALL) is the commonest form of ALL, and the commonest childhood tumor. It is a leading cause of childhood cancer death. It consists of multiple subtypes defined by genetic alterations. These are often chromosomal translocations that deregulate oncogenes or form fusion proteins. These alterations are disease initiating events and are associated with distinct patterns of leukemic cell gene expression. Most subtypes also have additional mutations that are important for cells to become fully leukemic.

Identifying these initiating genetic changes is very important to identify patients that are likely to respond or do poorly with conventional therapy (multiagent chemotherapy). Also, some identify new opportunities for targeted therapy. However, using standard genetic testing approaches such as chromosomal cytogenetics, about 30% of B-ALL patients don’t have a subtype classifying alteration.

MedicalResearch.com: What are the main findings?

Response: In this study we used RNA-sequencing of almost 2000 childhood and adult ALL samples, and a range of computational approaches to identify gene rearrangements, fusions, expression and mutation. We identified 23 different subtypes of ALL. Many were not previously identified as the alterations are not apparent on conventional genetic analysis. Also, several subtypes have not one but several gene rearrangements with a single gene that define a single subtype. We also identified several new subtypes where the defining change was not a gene rearrangement but a single point mutation: PAX5 P80R and IKZF1 N159Y. We proved mutations can be leukemic by establishing a mouse model of PAX5 P80R using CRISPR/Cas9 genome editing. The mice developed leukemia that was very similar to human B-ALL.

The new subtypes often had profound associations with outcome. e.g. DUX4 rearrangements were associated with excellent outcome in adults, as well as we had shown in children. Cases with rearrangements of BCL2 and MYC had a dismal outcome. 

MedicalResearch.com: What should readers take away from your report?

Response: Genomic analysis is now the standard of care for accurately identifying the range of subtypes of ALL. RNA-sequencing alone can be used to identify multiple different types of genomic alteration important in B-ALL. It is also suitable for use in clinical diagnostic labs. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Further work examining more older patients with leukemia; experimental studies examining how the new changes drive leukemia cell growth, and preclinical studies testing new agents in the new subtypes.

MedicalResearch.com: Is there anything else you would like to add?

Response: The study was a collaboration between St Jude, the Children’s Oncology Group, Eastern Cooperative Oncology Group (ECOG), The Alliance – Cancer and Leukemia Group B, and MD Anderson Cancer Center

The data are freely available. https://pecan.stjude.cloud/proteinpaint/study/PanALL

Citation: ASH18

Characterization of Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia

Monday, December 3, 2018:

Zhaohui Gu, PhD1, Michelle L. Churchman, PhD1*, Kathryn G. Roberts, PhD2, Ian Moore, MS1*, Xin Zhou, PhD3*, Joy Nakitandwe, PhD1*, Kohei Hagiwara, MD3*, Stephane Pelletier, PhD4*, Sebastian Gingras, PhD5*, Hartmut Berns, PhD6*, Debbie Payne-Turner1*, Ashley Hill, BS1*, Ilaria Iacobucci, PhD1, Lei Shi, PhD7*, Stanley Pounds, PhD7*, Cheng Cheng, PhD7*, Deqing Pei, MS7*, Chunxu Qu, PhD1*, Meenakshi Devidas, PhD8, Yunfeng Dai, PhD8*, Shalini C. Reshmi, PhD9, Julie Gastier Foster, PhD9*, Elizabeth A. Raetz, MD10, Michael J. Borowitz, MD, PhD11, Brent Wood, MD, PhD12, William L. Carroll, MD13, Patrick Zweider McKay, MD, PhD14*, Karen R. Rabin, MD, PhD15, Leonard A. Mattano, MD16, Kelly W. Maloney, MD17*, Alessandro Rambaldi, MD, PhD18*, Orietta Spinelli, PhD19*, Jerald Radich, MD20*, Mark D. Minden, MD, PhD21, Jacob M. Rowe, MD22*, Selina Luger, MD23, Mark R. Litzow, MD24, Martin S. Tallman, MD25, Janis Recevskis, PhD26*, Yanming Zhang27*, Ravi Bhatia, MD28, Jessica Kohlschmidt, PhD29, Krzysztof Mrózek, MD, PhD29, Clara D. Bloomfield, MD30, Wendy Stock, MD31, Steven M. Kornblau, MD32, Hagop M. Kantarjian, MD33, Marina Y. Konopleva, MD, PhD34, William E. Evans, PharmD35, Sima Jeha, MD36, Ching-Hon Pui, MD36, Jun J. Yang, PhD35, Elisabeth M. Paietta, PhD37*, James R. Downing, MD1, Mary V Relling, PharmD35, Jinghui Zhang3*, Mignon L. Loh, MD38, Stephen P. Hunger, MD39 and Charles G. Mullighan, MBBS, MD 1

Dec 5, 2018 @ 12:26 pm 

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