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 a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

• Keywords
• ALCL, PDX, brigatinib, crizotinib, tyrosine kinase inhibitors,
• MeSH
• Anaplastic Lymphoma Kinase MeSH
• Lymphoma, Large-Cell, Anaplastic * drug therapy   pathology   MeSH
• Child MeSH
• Heterografts MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Crizotinib pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Lung Neoplasms * drug therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * MeSH
• Organophosphorus Compounds pharmacology   therapeutic use   MeSH
• Receptor Protein-Tyrosine Kinases therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anaplastic Lymphoma Kinase MeSH
• brigatinib MeSH Browser
• Protein Kinase Inhibitors MeSH
• Crizotinib MeSH
• Organophosphorus Compounds MeSH
• Receptor Protein-Tyrosine Kinases MeSH

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

• Keywords
• ALCL, Apoptosis, NPM-ALK, PDGFRβ, STAT3, STAT5A, STAT5B,
• MeSH
• Anaplastic Lymphoma Kinase MeSH
• Lymphoma, Large-Cell, Anaplastic * genetics   pathology   MeSH
• Phosphorylation MeSH
• Carcinogenesis metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Receptor, Platelet-Derived Growth Factor beta * metabolism   pharmacology   MeSH
• Signal Transduction MeSH
• STAT3 Transcription Factor * metabolism   MeSH
• STAT5 Transcription Factor * genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anaplastic Lymphoma Kinase MeSH
• Receptor, Platelet-Derived Growth Factor beta * MeSH
• STAT3 protein, human MeSH Browser
• STAT3 Transcription Factor * MeSH
• STAT5 Transcription Factor * MeSH

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

• MeSH
• Hematologic Neoplasms * MeSH
• Humans MeSH
• Lymphoma * pathology   MeSH
• World Health Organization MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Lymphomas of the breast are rare neoplasms that arise from breast lymphoid tissue and are characterised by neoplastic B or T cells. Breast lymphomas arising from B cells include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, extra-nodal marginal zone lymphoma and Burkitt lymphoma. Anaplastic large cell lymphoma (ALCL) is of a T cell origin and both anaplastic lymphoma kinase (ALK)-positive and ALK-negative presentations have been noted in the breast. In addition, there is a more recently identified presentation of ALK-negative ALCL that arises around textured breast implants and is usually confined to a periprosthetic fibrous capsule. Here, we discuss the clinical presentations, histological and immunohistochemical features and treatment options for each type of primary breast lymphoma. We hope that this review will highlight the importance of the timely and accurate diagnosis of breast lymphoma in order to tailor the most appropriate treatment. We also wish to raise awareness of the breast implant-associated lymphomas, with the goal of stimulating work that will aid our understanding of their epidemiology and pathogenesis.

• Keywords
• BIA-ALCL, breast implant lymphoma, breast implants, breast lymphoma, non-Hodgkin lymphoma,
• Publication type
• Journal Article MeSH