-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1464 Interferon-Activated Gene Signatures Associate with Chemotherapy Resistance and Sensitivity to JAK-Inhibition in Refractory ETP-ALL

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers, and Minimal Residual Disease in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Genomics, Bioinformatics, Diseases, Immune mechanism, Lymphoid Malignancies, Biological Processes, Technology and Procedures, Measurable Residual Disease
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Jason Xu1,2, Jonathan Sussman3*, Austin Yang4*, Satoshi Yoshimura, MD5*, Changya Chen2, Omar Elghawy, MD6*, Tiffaney Vincent, BS7*, Caroline Diorio, MD2, Shovik Bandyopadyay4*, Jianzhong Hu, BS8*, Alexander Lai Li9*, Gregory M. Chen, MD, PhD10*, Chia-Hui Chen11*, Rawan Shraim, PhD2*, Haley Newman, MD2, Yang Ding11, Elizabeth Li, MD12*, Wenbao Yu11*, Anusha Thadi9*, Kyung Jin Ahn4*, Petri Pölönen, PhD13, Abdelrahman Elsayed8*, David Frank, MD, PhD14*, Elizabeth A. Raetz, MD15, Mignon L. Loh, MD, PhD16, Brent L. Wood, MD, PhD17, Stuart S. Winter, MD18, Kimberly P. Dunsmore, MD19*, Meenakshi Devidas, PhD, MBA20, Chunxu Qu13*, Stanley Pounds, PhD21*, Stephen P. Hunger, MD22, Charles G. Mullighan, MBBS, MSc, MD13, Jun J. Yang, PhD5, Kai Tan, PhD23 and David T. Teachey, MD24

1Perelman School of Medicine, Philadelphia, PA
2Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
3Perelman School of Medicine, Philadelphia
4Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
5Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
6Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
7The Children's Hospital of Philadelphia, Philadelphia, PA
8St. Jude Children's Research Hospital, Memphis, TN
9Children's Hospital of Philadelphia, Philadelphia
10Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
11Children's Hospital of Philadelphia, Philadelphia, PA
12Children’s Hospital of Philadelphia, Philadelphia, PA
13Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
14Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA
15Department of Pediatrics, NYU Langone Health, New York, NY
16Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, Fred Hutch Cancer Center, University of Washington, Seattle, WA
17Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
18Cancer and Blood Disorders, Children's Minnesota, Eagan, MN
19University of Virginia Health Sciences Center, Charlottesville, VA
20St Jude Children's Research Hospital, Memphis, TN
21Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
22Division of Oncology, Childrens Hospital of Philadelphia, Philadelphia
23Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
24Division of Oncology, Children's Hospital of Philadelphia, Rutledge, PA

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive lymphoid malignancy in which optimal therapeutic approaches for relapsed/refractory disease and biomarkers for upfront risk stratification are currently unknown.We previously reported integrated scRNA and scATAC-seq analysis on 40 T-ALL cases that identified a BCL2-inhibitor sensitive bone-marrow progenitor-like (BMP-like) tumor sub-population that is highly resistant to conventional therapy and found across all immunophenotypic subtypes of T-ALL. Further analysis of blasts from BMP-high and BMP-low T-ALL patients revealed one outlier patient (PASKMG) within ETP-ALL cases that had refractory disease (Day 29 bone marrow MRD >20%) despite a low proportion of BMP-like blasts. Notably, this patient was the only patient that harbored a BMP-low signature (<10% blasts in BMP-like state) and T-lineage-high signature (>50% blasts in pro-T/pre-T state) with poor response to conventional therapy. We hypothesized that transcriptomic and epigenetic characterization of PASKMG would elucidate an additional novel mechanism of treatment failure.

Results

Differential expression analysis comparing PASKMG leukemic blasts to other ETP blasts from patients with induction failure (n=5, all BMP-high) revealed a strong upregulation of 35 interferon-alpha related gene products, including 19 genes within the STAT1-driven IFN-related DNA damage resistance signature (IRDS) previously identified in chemotherapy/radiation refractory solid tumors. Intersection of scRNA and scATAC data revealed STAT1, STAT5B, STAT3, IRF7/9 to be top differentially expressed transcription factors (TFs) with differentially accessible TFs motifs, consistent with STAT activation seen in IRDS expressing carcinomas. Interestingly, our analysis also identified a GATA2+, CD117+, CD33+, CD63+ MEP-like subpopulation with high expression of IRDS genes. This leukemia subpopulation was retained in PDX models of PASKMG and harbored a strong inflammatory signature with enrichment of neutrophil degranulation and cell adhesion pathways.

We next hypothesized that tumor-intrinsic IRDS expression could associate with a unique leukemic micro-environment. Indeed, across non-leukemic cell subsets, we detected expression of antiviral gene expression associated with interferon signaling, including upregulation of HLA components and PLCG2 signaling. Compared to 21 other single-cell profiled ETP-ALL BM aspirates, PASKMG harbored a uniquely inflammatory microenvironment dominated by NK and effector T-cell subsets, rather than by non-activated Naïve-T cells.

Prior studies have indicated unique sensitivity of IRDS+ solid tumors to JAK/STAT inhibition. While JAK-inhibition has been explored as a targeted therapy for T-ALL, initial results indicate highly heterogenous responses amongst patients. To test if IRDS could be a biomarker of JAK inhibitor sensitivity in refractory ETP-ALL, we expanded blasts from PASKMG and other ETP-ALL patients in patient derived xenograft models. Single-cell transcriptomic analysis of PDX expanded blasts indicated strong retention of IRDS signatures unique to PASKMG. Within in-vitro drug screening and in-vivo experiments, we found that PASKMG had markedly increased sensitivity to multiple JAK inhibitors compared to other ETP-ALL and T-ALL.

Discussion

Here, we report the identification of an IRDS resistance signature in leukemia that is associated with targetable JAK/STAT signaling, inflammatory microenvironment, mast-cell-like tumor subpopulation, and increased sensitivity to JAK inhibition. To our knowledge, this is the first report of IFN-related DNA damage resistance signature in liquid tumors; in contrast, in solid tumors, IRDS positivity is known to be a marker of chemo and radiation resistance. Our PDX data indicating unique vulnerability of IRDS+ ETP-ALL to JAK-inhibitors are translationally promising for successful implantation of JAK/STAT inhibitors in T-ALL. We propose further study of interferon activation in T-ALL and other leukemias for prospective identification of patients that may benefit from JAK inhibitor targeted therapy.

--

*JX, JS, and AY contributed equally to this work

**DT and KT co-supervised this work

Disclosures: Wood: Cellnomics LLC: Current equity holder in private company; Amgen: Consultancy. Hunger: Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria; Jazz Pharmaceuticals: Honoraria; Servier US: Honoraria. Teachey: BEAM Therapeutics: Research Funding; NeoImmune Tech: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH