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565 Characterization of Novel Subtypes in B Progenitor Acute Lymphoblastic LeukemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: ALL Taxonomy, Pathway Activation and Signaling
Hematology Disease Topics & Pathways:
Diseases, Leukemia, ALL, Adult, Biological Processes, Pediatric, Technology and Procedures, Young Adult, cytogenetics, Study Population, Lymphoid Malignancies, Clinically relevant, genomics, NGS, RNA sequencing, WGS
Monday, December 3, 2018: 7:00 AM
Room 25B (San Diego Convention Center)

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

1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
2St. Jude Children's Research Hospital, Memphis, TN
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
4Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
5Department of Immunology, University of Pittsburgh, Pittsburgh, PA
6Department of Transgenic Core Facility, St. Jude Children’s Research Hospital, Memphis, TN
7Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
8Department of Biostatistics, University of Florida, Gainesville, FL
9Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH
10Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders, New York, NY
11Division of Hematologic Pathology, Johns Hopkins University, Baltimore, MD
12Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
13Perlmutter Cancer Center at NYU Langone Health, New York University, New York, NY
14ImmunoGen, Inc., Waltham, MA
15Pediatric Hematology/Oncology, Baylor College of Medicine, Houston, TX
16HARP Pharma Consulting, Mystic, CT
17University of Colorado School of Medicine and Children’s Hospital, Aurora, CO
18University of Milan and Azienda Socio Sanitaria Territoriale, Papa Giovanni XXIII, Bergamo, Italy
19Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy
20Fred Hutchinson Cancer Research Center, Seattle, WA
21Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
22Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
23Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, PA
24Division of Hematology, Mayo Clinic, Rochester, MN
25Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
26Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
27Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY
28Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL
29The Ohio State University Comprehensive Cancer Center, Columbus, OH
30Comprehensive Cancer Center, The Ohio State University, Columbus, OH
31University of Chicago Medical Center, Chicago, IL
32Department of Leukemia, MD Anderson Cancer Center, Houston, TX
33Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
34Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
35Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
36Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
37Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
38Department of Pediatrics, UCSF Benioff Children’s Hospital and the Helen Diller Family, San Francisco, CA
39Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA


B progenitor acute lymphoblastic leukemia (B-ALL) is a leading cause of childhood cancer death. Many chimeric genes have been identified and led to a refined classification of B-ALL and tailored therapies. Still, up to 30% of B-ALL cannot be classified into established subtypes, and the outcome for many is poor.


To identify novel subtypes of B-ALL, we performed integrative genomic analysis including transcriptome sequencing (RNA-seq) of 1,988 cases from St. Jude, Children’s Oncology Group and adult cooperative group studies and analyzed chromosomal rearrangements, gene-expression profiles (GEP), somatic mutations and chromosome-level copy-number alterations. Cases lacking known or putative subtype-defining alterations underwent whole genome sequencing. Effects on proliferation and transformation of novel lesions were assessed by retroviral expression in cell lines and point-mutation knock-in mice using CRISPR/Cas9 genome editing.


Using integrated genetic alterations and gene expression profiling, we classified 23 B-ALL subtypes (Table and Figure). Three groups included cases with similar GEP as canonical subtypes (ETV6-RUNX1, KMT2A-rearranged, and ZNF384-rearranged), but lacking the expected drivers (e.g., ETV6-RUNX1-like, n=42). Eighteen cases (0.9%) had rearrangements of BCL2, MYC and/or BCL6 showing a distinct GEP; they were mostly adults (n=16) with very poor outcome. These alterations, rarely seen in ALL, are identical to those observed in “double/triple hit” lymphoma, and are of pre-B immunophenotype. Eight cases with tightly clustered GEP comprised a novel subtype defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to perturb IKZF1 function, with distinct nuclear mislocalization and induction of aberrant intercellular adhesion.

We identified two subtypes with distinct GEP characterized by PAX5 alterations. One, herein termed PAX5 altered (PAX5alt), comprised 148 (7.4%) cases, 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 and different alteration types were mutually exclusive. Other PAX5 alterations, including deletions and large-scale amplifications were also assessed using SNP array, but were not enriched in the PAX5alt group. Clinically, PAX5alt pediatric and adult patients had favorable (96.8±3.2%) and intermediate (42.1±10.2%) 5-year overall survival (OS), respectively. The other GEP distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. In 30 of these cases, PAX5 P80R was homozygous due to deletion of the wild-type (WT) PAX5 allele or copy-neutral loss of heterozygosity. Of the other 14 cases with heterozygous PAX5 P80R mutations, 13 had a second frameshift (n=7), nonsense (n=2) or deleterious missense (n=4) PAX5 mutation. Four of the remaining 1,944 cases also had the PAX5 P80R mutation, but all were heterozygous with preservation of a WT PAX5 allele, consistent with the notion that homozygous or compound heterozygous PAX5 P80R mutation is the hallmark of this subtype. Adult PAX5 P80R cases (n=14) showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). To examine the effects of PAX5 P80R on B-cell maturation, WT PAX5, PAX5 P80R, V26G and P34Q were expressed in Pax5-/- lineage-depleted bone marrow cells. Expression of WT PAX5, PAX5 V26G and P34Q resulted in near complete rescue of B cell differentiation; however, expression of PAX5 P80R blocked the differentiation at the pre-pro-B stage of B-cell maturation. Further, Pax5 P80R heterozygous or homozygous mice developed pre-B-ALL with a median latency of 166 and 87 days, respectively, with heterozygous mice acquiring alterations on the second allele. In contrast, Pax5+/- mice, and those harboring G183S mutation observed in familial leukemia, do not spontaneously develop B-ALL.


These results show the utility of transcriptome sequencing in defining subtypes and founding genetic alterations in B-ALL, provide a revised taxonomy of the disease across the age spectrum, and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

Disclosures: McKay: ImmunoGen Inc.: Employment. Tallman: BioSight: Other: Advisory board; AbbVie: Research Funding; AROG: Research Funding; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board. Stock: Jazz Pharmaceuticals: Consultancy. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria. Konopleva: Stemline Therapeutics: Research Funding. Relling: Shire Pharmaceuticals: Research Funding. Mullighan: Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.

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