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CHRONIC LYMPHOCYTIC LEUKEMIA

RPPA-based proteomics recognizes distinct epigenetic signatures in chronic lymphocytic leukemia with clinical consequences

Leukemia volume 36, pages 712–722 (2022)Cite this article

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Abstract

The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.

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Fig. 1: HME and HMM are expressed in proteomic signatures in CLL.
Fig. 2: Kaplan–Meier analysis of overall survival (OS) and time to first treatment (TTFT) per protein signature cluster for CLL patients.
Fig. 3: Overall survival (OS) after first treatment and time to second treatment (TTST) durations after different treatment regimes according to cluster membership in CLL patients only.
Fig. 4: Individual protein expression according to proteomic signature.
Fig. 5: Known protein–protein associations of the 384 proteins on the CLL RPPA, including 37 HME (big nodes).

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Author notes

  1. These authors contributed equally: Anneke D. van Dijk, Ti’ara L. Griffen.

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, University Medical Center Groningen, Groningen, the Netherlands

    Anneke D. van Dijk, Fieke W. Hoff & Eveline S. J. M. de Bont

  2. Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, USA

    Ti’ara L. Griffen & James W. Lillard Jr

  3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yihua H. Qiu, Endurance Toro, Kevin Ruiz, Jan A. Burger, William Wierda & Steven M. Kornblau

  4. Department of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Peter P. Ruvolo

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Contributions

ADvD, TLG, JWL, ESJMdB, and SMK designed and supervised the study. SMK, JAB, and WW collected data, ADvD, TLG, FWH, ET, KR, PPR, and YHQ performed research. ADvD and SMK analyzed data and wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Anneke D. van Dijk.

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van Dijk, A.D., Griffen, T.L., Qiu, Y.H. et al. RPPA-based proteomics recognizes distinct epigenetic signatures in chronic lymphocytic leukemia with clinical consequences. Leukemia 36, 712–722 (2022). https://doi.org/10.1038/s41375-021-01438-4

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