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  • Acute lymphoblastic leukemia
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HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia

Leukemia volume 35, pages 2086–2091 (2021)Cite this article

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Acute lymphoblastic leukemia derived from B-cell progenitors (proB ALL) is the most frequently diagnosed type of childhood cancer [1]. Current 5-year overall survival (OS) rates for pediatric B-ALL approach ∼90%. However, proB ALL in infants (<1 year of age) is associated with an aggressive early clinical presentation, suboptimal response to chemotherapy and unfavorable clinical outcome [2]. Importantly, chromosomal rearrangements involving the mixed-lineage leukemia gene (KMT2A, also known as MLL) account for ∼80% of proB ALL diagnoses [3], and clinical outcome of proB ALL infants with MLL rearrangements (MLLr), especially with t(4;11) translocation, is particularly dismal [4,5,6]. MLLr is an initiating oncogenic driver in proB ALL, occurring prenatally during fetal hematopoiesis [2, 7, 8]. This fact, coupled to a short latency, suggests that MLLr might suffice for leukemogenesis. In support of this hypothesis, genome-wide DNA sequencing of proB ALL infants has revealed a sparse mutational landscape [6], reinforcing the idea that MLLr proB ALL requires very few cooperating mutations to lead to overt leukemia.

The fine-tuned generation of distinct hematopoietic cell populations is of utmost relevance in leukemia research. There is increasing evidence that lymphocyte-specific transcription factors (TFs) not only induce B-cell-specific genes, but also repress lineage-specific or functionally inappropriate genes, ensuring the formation and identity of B lymphocytes [9]. The aberrant expression of and/or mutations in many of these TFs have been linked to the onset of hematopoietic malignancies [10]. Additionally, histone deacetylases (HDACs) have emerged as crucial transcriptional repressors at diverse stages of immune cells differentiation and, therefore, have been suggested as potential therapeutic candidates for proB ALL [11]. However, our understanding of how individual HDACs contribute to cancer is limited, partly because their contribution is not restricted to an overexpression context. Toward alleviating this, we have previously reported the role of HDAC7, a class IIa HDAC, in early B lymphocyte development, where it silences lineage-inappropriate genes at the proB lymphocyte stage [12]. Here, we report HDAC7 as an important contributor to the pathogenesis of t(4;11) leukemia. It is strongly underexpressed in t(4;11) proB ALL infants and its low expression correlates with a significantly poorer clinical outcome. The identification of HDAC7 as a clinical prognostic marker for t(4;11) leukemia opens new therapeutic avenues in proB ALL.

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Fig. 1: HDAC7 exerts a leukemia suppressive phenotype in t(4;11) proB ALL cells, and its absence associates with poor prognosis in proB ALL infants.
Fig. 2: Enforced overexpression of HDAC7 partially reverts the expression pattern of genes affected by t(4;11) translocation in proB ALL.

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Acknowledgements

The authors wish to thank all clinical and laboratory members of the Interfant treatment protocol for their support and accessibility of samples/clinical data. We thank CERCA Programme/Generalitat de Catalunya for institutional support. This paper was funded by grants to MP by the Spanish Ministry of Science, Innovation and Universities (SAF2017-87990-R and EUR2019-103835) and elaborated at the Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona) and IDIBELL Research Institute (L’Hospitalet de Llobregat, Barcelona). OdB is funded by a Juan de la Cierva—Formación fellowship from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-32430). AM is funded by the Spanish Ministry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigación (AEI), through grant PRE2018-083183 (cofunded by the European Social Fund). Work in PM and CB’s lab was supported by the European Research Council (CoG-2014646903), the Spanish Ministry of Economy and Competitiveness (SAF-2016-80481-R), Uno entre Cien Mil Foundation, the Leo Messi Foundation, the Asociación Española Contra el Cáncer (AECC-CI-2015), and the ISCIII/FEDER (PI17/01028). We thank Juan Ramón Tejedor for the analysis of ChIP sequencing data.

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Authors and Affiliations

  1. Lymphocyte Development and Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Ctra. de Can Ruti, Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain

    Oriol de Barrios, Alba Azagra, Olga Collazo, Ainara Meler & Maribel Parra

  2. Cellular Differentiation Group, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain

    Oriol de Barrios, Alba Azagra, Olga Collazo, Ainara Meler & Maribel Parra

  3. Biomedical Sciences Research Center “Alexander Fleming”, 16672, Vari, Greece

    Alexandros Galaras & Pantelis Hatzis

  4. Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece

    Alexandros Galaras

  5. Josep Carreras Leukaemia Research Institute, School of Medicine, University of Barcelona, 08036, Barcelona, Spain

    Juan L. Trincado, Antonio Agraz-Doblas, Clara Bueno & Pablo Menéndez

  6. Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC, Santander, Spain

    Antonio Agraz-Doblas & Ignacio Varela

  7. Department of Pediatric Hematology, A. Trousseau Hospital, Paris, France

    Paola Ballerini

  8. Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy

    Giovanni Cazzaniga & Paola De Lorenzo

  9. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Ronald W. Stam

  10. Interfant Trial Data Center, University of Milano-Bicocca, Monza, Italy

    Paola De Lorenzo & Maria Grazia Valsecchi

  11. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Pablo Menéndez

  12. CIBER-ONC-ISCIII, Barcelona, Spain

    Pablo Menéndez

Authors
  1. Oriol de Barrios
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Contributions

OdB designed and performed most of the experimental work of the study. AG, JLT, AA-D, and PH performed and interpreted bioinformatics data analysis. AA, OC, and AM carried out some of the experimental work. CB, PB, GC, RWS, IV, and PM supplied critical materials to the study. PdL and MGV performed the analysis of patientsʼ outcome. PM assisted in the conception and supervision of the study. OdB and MP wrote the paper. MP obtained funding, conceived and supervised the study. All authors critically reviewed the paper.

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Correspondence to Maribel Parra.

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The authors declare no competing financial interest. PM is founder of OneChain Immunotherapeutics SL.

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de Barrios, O., Galaras, A., Trincado, J.L. et al. HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia. Leukemia 35, 2086–2091 (2021). https://doi.org/10.1038/s41375-020-01097-x

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