Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia

MedicalResearch.comInterview with:

Zhaohui Gu, PhD
Postdoctoral Research Associate
 St. Jude Children’s Research Hospital, TN

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

Response:B-progenitor acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy and the leading cause of childhood cancer death. B-ALL includes multiple subtypes that are defined by distinct genetic alterations and that play an important role in diagnosis, prognosis and therapy of patients.  Advances in transcriptome sequencing (RNA-seq)have helped researchers discover additional subtypes and driver mutations inB-ALL and identify possible new therapeutic targets.  Still, up to 30% of B-ALL cases do not fit into established subtypes. These patients lack targeted therapeutic approaches and commonly relapse.

Fort his study, we used integrated genomic analysis of 1,988 childhood and adult cases to revise the classification system of B-ALL. The system includes eight new subtypes and a total of 23 B-ALL subtypes. The subtypes are defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Many show a marked variation in prevalence according to age.

The newly identified subtypes included one (n=18) defined by rearrangements of gene BCL2, MYC and/or BCL6 anda distinctive gene expression profile (GEP). Patients in this subtype were mostly adults (n=16) with very poor outcomes.

Another novel subtype was defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to disrupt IKZF1 function, with distinct nuclear mis-localization and induction of aberrant intercellular adhesion. There were eight cases in this subtype that shared highly similar GEPs.

We also identified two subtypes with distinct GEP and characterized by PAX5 alterations. One, PAX5 altered (PAX5alt), included 148 cases. PAX5alt was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases. The second distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. Bi-allelic PAX5 alterations were commonly seen in this subtype in the form of PAX5 P80R coupled with a second sequence mutation or deletion of the wild-type PAX5 allele.

Adult PAX5 P80R cases showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). In addition, Pax5 P80R heterozygous and homozygous mice developed B lineage leukemia with a median latency of 166 and 87 days, respectively.  The heterozygous mice acquired alterations on the second allele, which faithfully recapitulated the condition of the patient leukemia.

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

Response: Identification of subtypes accurately is very important for diagnosis, intensity-tailored therapy, and to identify targetable lesions. In this large scale genomic study, we demonstrated the power of using RNA-seq to classifying B-ALL and established a revised B-ALL taxonomy with 23 distinct subtypes. We identified 8 novel subtypes, including two defined by PAX5 alterations. Through in vitro and in vivo experiments, we demonstrated that PAX5 P80R could impair B cell differentiation and initiate leukemia.

Together with the subtype defined by IKZF1 N159Y mutation, we showed for the first time that transcription factor missense mutations could be a subtype defining genetic lesions.

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

Response:B-ALL classification has been conventionally used in scientific research and clinicaltreatment. However, due to the complexity of genetic alterations and geneexpression profile analysis, a comprehensive and robust classification is stillchallenging for many researchers and clinicians. This study establishes anRNA-seq data based B-ALL classification pipeline, which could assign over 90%of the B-ALL cases into distinct subtypes. The raw sequence data and well-curatedgenetic information of 1,988 B-ALL case have been deposited to public database(https://www.ebi.ac.uk/ega/). The dataare also accessible through an interactive St. Jude data portal (https://pecan.stjude.cloud/proteinpaint/study/PanALL),which serve as invaluable resource for future research and clinical diagnosis.

We have identified eight new subtypes in previously uncategorized B-other cases. We described each subtypes’ gene expression signatures, driver genetic lesions and clinical outcomes, but in-depth functional studies and development of customized treatments for the novel subtypes are still needed. The genetic background of patients in each subtype is similar, making it easier to evaluate and compare patients’ response to specific treatments. That should potentially speed-up the development of more effective treatment for these previously uncategorized cases.

Despite the progress, about 6% of the B-ALL cases still cannot be classified into any subtypes. We propose to perform more comprehensive genomic analysis, including whole genome sequence, to identify the hidden driver lesions. Ultimately, the goal is to classify all B-ALL patients into distinct subtypes and assign customized regimens for them.

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

Response: This was an international effort and multiple institutional collaborative project. The participants were St. Jude Children’s Research Hospital, The Children’s Oncology Group, ECOG-ACRIN Cancer Research Group, Cancer and Leukemia Group B, M.D. Anderson Cancer Center, University of Toronto, Northern Italian Leukemia Group, Southwestern Oncology Group, Medical Research Council UK and City of Hope.

Citation: Abstract presented at the 2018 ASH abstract Publication

Number: 565                                                             Submission ID: 111219

Title: Characterization of Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia

Zhaohui Gu, PhD1, Michelle L. Churchman, PhD1, Kathryn G. Roberts, PhD1, Ian Moore, MS1, Xin Zhou, PhD2, Joy Nakitandwe, PhD1, Kohei Hagiwara, MD2, Stephane Pelletier, PhD3, Sebastien Gingras, PhD4, Hartmut Berns, PhD5, Debbie Payne-Turner, BS1, Ashley Hill, BS1, Ilaria Iacobucci, PhD1, Lei Shi, PhD6, Stanley Pounds, PhD6, Cheng Cheng, PhD6, Deqing Pei, MS6, Chunxu Qu, PhD1, Meenakshi Devidas, PhD7, Yunfeng Dai, MS7, Shalini C. Reshmi, PhD8, Julie Gastier-Foster, PhD8, Elizabeth A. Raetz, MD9, Michael J. Borowitz, MD, PhD10, Brent L. Wood, MD, PhD11, William L. Carroll, MD12, Patrick A. Zweidler-McKay, MD, PhD13, Karen R. Rabin, MD, PhD14, Leonard A. Mattano, MD15,Kelly W. Maloney, MD16, Alessandro Rambaldi, MD17, Orietta Spinelli, PhD17, Jerald P. Radich, MD18, Mark D. Minden, MD, PhD19, Jacob M. Rowe, MD20, Selina Luger, MD21, Mark R. Litzow, MD22, Martin S. Tallman, MD23, Janis Racevskis, PhD24, Yanming Zhang, MD25, Ravi Bhatia, MD26, Jessica Kohlschmidt, PhD27, Krzysztof Mrózek, MD, PhD27, Clara D. Bloomfield, MD27, Wendy Stock, MD28, Steven Kornblau, MD29, Hagop M. Kantarjian, MD29, Marina Konopleva, MD29, Williams Evans, PharMD30, Sima Jeha, MD31, Ching-Hon Pui, MD31, Jun Yang, PhD30, Elisabeth Paietta, PhD24, James Downing, MD1, Mary V. Relling, PharMD30, Jinghui Zhang, PhD2, Mignon L. Loh, MD32, Stephen P. Hunger, MD33, Charles Mullighan, MBBS, MD1

1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN

2Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN

3Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN

4Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261

5Department of Transgenic Core Facility, St. Jude Children’s Research Hospital, Memphis, TN

6Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN

7Department of Biostatistics, University of Florida, Gainesville, FL

8Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH

9Division of Pediatric Hematology-Oncology, New York University, New York, NY 10016,

10Division of Hematologic Pathology, Johns Hopkins University, Baltimore, MD

11Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA

12Perlmutter Cancer Center, NYU-Langone Health, New York, NY

13ImmunoGen, Inc, Waltham, Massachusetts

14Baylor College of Medicine, Houston, TX

15HARP Pharma Consulting, Mystic, CT

16University of Colorado School of Medicine and Children’s Hospital, Aurora CO

17Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy

18Fred Hutchinson Cancer Research Center, Seattle, WA 

19Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

20Hematology, Shaare Zedek Medical Center, Jerlem, Israel 

21Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

22Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN

23Memorial Sloan Kettering Cancer Center, New York, NY

24Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY

25Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center

26Division of Hematology-Oncology, University of Birmingham, Alabama

27Comprehensive Cancer Center, The Ohio State University, Columbus, OH 

28University of Chicago Medical Center, Chicago, IL 

29Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 

30Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN

31Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN

32Department of Pediatrics, UCSF Benioff Children’s Hospital and the Helen Diller Family

33Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Dec 12, 2018 @ 4:01 pm

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