Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes.

• MeSH
• Anaplastic Lymphoma Kinase * metabolism   genetics   MeSH
• Lymphoma, Large-Cell, Anaplastic * drug therapy   pathology   genetics   metabolism   MeSH
• Benzamides pharmacology   MeSH
• Histone Deacetylase 1 * genetics   antagonists & inhibitors   physiology   metabolism   MeSH
• Histone Deacetylase 2 genetics   MeSH
• Histone Deacetylase Inhibitors * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Mice MeSH
• Pyridines pharmacology   MeSH
• Genes, Tumor Suppressor * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alk protein, mouse MeSH Browser
• Anaplastic Lymphoma Kinase * MeSH
• Benzamides MeSH
• entinostat MeSH Browser
• Hdac1 protein, mouse MeSH Browser
• Histone Deacetylase 1 * MeSH
• Histone Deacetylase 2 MeSH
• Histone Deacetylase Inhibitors * MeSH
• Pyridines MeSH

BACKGROUND: Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory. METHODS: We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models. RESULTS: Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients. CONCLUSIONS: These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.

• MeSH
• Lymphoma, Large-Cell, Anaplastic * genetics   pathology   drug therapy   MeSH
• Phenotype MeSH
• Cadherins * genetics   MeSH
• Humans MeSH
• Mutation * MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prognosis MeSH
• Exome Sequencing MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cadherins * MeSH

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

• MeSH
• Anaplastic Lymphoma Kinase genetics   metabolism   MeSH
• Lymphoma, Large-Cell, Anaplastic * genetics   metabolism   pathology   MeSH
• Child MeSH
• Adult MeSH
• Janus Kinases metabolism   MeSH
• Carcinogenesis genetics   MeSH
• Humans MeSH
• Cell Transformation, Neoplastic MeSH
• Signal Transduction * genetics   MeSH
• STAT3 Transcription Factor genetics   MeSH
• STAT Transcription Factors metabolism   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anaplastic Lymphoma Kinase MeSH
• Janus Kinases MeSH
• STAT3 protein, human MeSH Browser
• STAT3 Transcription Factor MeSH
• STAT Transcription Factors MeSH

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

• MeSH
• Anaplastic Lymphoma Kinase MeSH
• Lymphoma, Large-Cell, Anaplastic * drug therapy   genetics   pathology   MeSH
• Endothelial Cells metabolism   MeSH
• Phosphatidylinositol 3-Kinases MeSH
• Protein Kinase Inhibitors pharmacology   therapeutic use   MeSH
• Tyrosine Kinase Inhibitors MeSH
• Crizotinib pharmacology   therapeutic use   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment MeSH
• Lung Neoplasms * drug therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   MeSH
• Receptors, CCR7 genetics   MeSH
• Receptor Protein-Tyrosine Kinases metabolism   MeSH
• Protein-Tyrosine Kinases MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Anaplastic Lymphoma Kinase MeSH
• CCR7 protein, human MeSH Browser
• Phosphatidylinositol 3-Kinases MeSH
• Protein Kinase Inhibitors MeSH
• Tyrosine Kinase Inhibitors MeSH
• Crizotinib MeSH
• Receptors, CCR7 MeSH
• Receptor Protein-Tyrosine Kinases MeSH
• Protein-Tyrosine Kinases MeSH

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

• Keywords
• anaplastic large cell lymphoma, chemotherapy, nucleophosmin1-anaplastic lymphoma kinase, paediatric cancer, resistance,
• Publication type
• Journal Article MeSH
• Review MeSH