Chronic lymphocytic leukaemia (CLL) is a genetically, morphologically and phenotypically heterogeneous chronic disease with clinical variability between patients. Whether the significant heterogeneity of cell size within the CLL population contributes to the heterogeneous features of this disease has not been investigated. The present study aimed to characterise the phenotypic and functional properties of two subpopulations of typical CLL cells that differ in cell size: small (s-CLL) and large (l-CLL) CLL cells delineated by forward scatter cytometry. The s-CLL cells were characterised by the CD5lowCXCR4hi phenotype, while the l-CLL cells were characterised by the CD5hiCXCR4dim phenotype and indicated a higher expression of CXCR3, CD20, CD38 and HLA-DR. The l-CLL cells displayed higher migration activity towards CXCL12, a tendency towards a higher proliferation rate and an increased capacity to produce IgM in the presence of CpG compared with s-CLL cells. When stimulated with CpG and CXCL12, l-CLL cells were characterised by a higher polarisation phenotype and motility than s-CLL cells. Our study revealed that the differences in CLL cell size reflected their activation status, polarisation and migratory abilities. Our data provide evidence of the importance of cell-size heterogeneity within a CLL pool and the dynamics of cell-size changes for disease pathogenesis, thus deserving further investigation.

• Keywords
• cell-size heterogeneity, chronic lymphocytic leukaemia, migration, polarisation, pool of leukemic cells,
• Publication type
• Journal Article MeSH

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

• MeSH
• Lymphoma, Large-Cell, Anaplastic drug therapy   genetics   metabolism   pathology   MeSH
• Ki-1 Antigen genetics   metabolism   MeSH
• Immunoconjugates pharmacology   MeSH
• Interleukin-15 pharmacology   MeSH
• Interleukin-2 pharmacology   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Interleukin-2 Receptor alpha Subunit genetics   immunology   metabolism   MeSH
• Receptors, Interleukin-2 genetics   immunology   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Regulatory Sequences, Nucleic Acid MeSH
• Repressor Proteins genetics   metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Basic-Leucine Zipper Transcription Factors genetics   metabolism   MeSH
• Cell Survival drug effects   MeSH
• Xenograft Model Antitumor Assays 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
• Ki-1 Antigen MeSH
• BATF3 protein, human MeSH Browser
• IL2RA protein, human MeSH Browser
• Immunoconjugates MeSH
• Interleukin-15 MeSH
• Interleukin-2 MeSH
• Interleukin-2 Receptor alpha Subunit MeSH
• Receptors, Interleukin-2 MeSH
• Repressor Proteins MeSH
• Basic-Leucine Zipper Transcription Factors MeSH

Chimeric antigen receptor (CAR) T-cell therapy has already achieved remarkable remissions in some difficult-to-treat patients with B-cell malignancies. Although the clinical experience in chronic lymphocytic leukemia (CLL) patients is limited, the proportion of remissions reached in this disease is clearly the lowest from the spectrum of B-cell tumors. In this review, we discuss the antigenic targets exploited in CLL CAR-T therapy, the determinants of favorable responses, as well as the mechanisms of treatment failure specific to this disease.

• Keywords
• CD19, chimeric antigen receptor, chronic lymphocytic leukemia, immunotherapy,
• MeSH
• Antigens, CD19 immunology   MeSH
• B-Lymphocytes immunology   MeSH
• Receptors, Chimeric Antigen immunology   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell immunology   therapy   MeSH
• Immunotherapy, Adoptive methods   MeSH
• Remission Induction MeSH
• Humans MeSH
• T-Lymphocytes immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antigens, CD19 MeSH
• CD19 molecule, human MeSH Browser
• Receptors, Chimeric Antigen MeSH