Suchergebnisse

Funding Information: Conflict of interest SM has received honoraria and research funding from Novartis, Pfizer and Bristol-Myers Squibb (not related to this study). SAA has received research funding from Incyte. SB is a member of Member of the advisory board of Qiagen, Novartis, and Cepheid and has received research funding from Novartis, honoraria from Novartis, Qiagen, Cepheid, and Bristol-Myers Squibb and support from the National Health and Medical Research Council of Australia APP1117718 and APP1104425, the Ray and Shirl Norman Cancer Research Trust, and the Royal Adelaide Hospital Research Foundation. The other authors declare that they have no conflict of interest. Funding Information: Funding This work was supported by Academy of Finland (Grant No. 292605 and 287224), the Finnish Funding Agency for Innovation (Dnro 6113/31/2016), Finnish special governmental subsidy for health sciences, research and training, Signe and Ane Gyllenberg Foundation, Finnish Cultural Foundation, Nordic Cancer Union, Helsinki Institute of Life Science, Cancer Foundation Finland, Relander Foundation, Incyte Nordic Hematology grant, and Finnish Cancer Institute. Publisher Copyright: © 2020, The Author(s). ; Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1mut patients to be highly responsive for mTOR-, BCL2-, and VEGFRinhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1−/− and heterozygous RUNX1−/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1mut BP-CML patients. ; Peer reviewed

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4 T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4 T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies. + + ; This work was supported by the European Research Council (M-IMM project), Academy of Finland (Decisions 287224, 314442), Finnish special governmental subsidy for health sciences, research and training, Sigrid Juselius Foundation, Instrumentarium Science foundation, Helsinki Institute of Life Sciences Fellow funding, Cancer Foundation Finland, and Finnish Cancer Institute. T.L. was supported by the Academy of Finland (Decisions 311081 and 314557). This study was supported by Finnish Functional Genomics Center, University of Turku, Åbo Akademi University and Biocenter Finland. IT Center for Science LTD (CSC) is acknowledged for their help and computing resources.

T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules. ; Funding for this work was by grant PI015/02085 and PI18/01163 from the Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain to CMC who was also cofinanced by FEDER funds. CCM and FT were supported by RTC-2015-3318-1 (Ministerio de Economía y Competitividad, Spain). MH was funded by the German Research Foundation (DFG; HE3553/ 4–2) as part of the collaborative research group on mature T-cell lymphomas, "CONTROL-T" (FOR1961). The José Carreras Leukemia Foundation (03F/2016), the Köln Fortune Program, and the Fritz Thyssen foundation (10.15.2.034MN) supported MH and AS. The Köln Fortune Program also supported LW. SM was supported by the Finnish Cancer Organizations, the Finnish Cancer Institute, Academy of Finland and the Sigrid Juselius Foundation. SM and MH are supported by the ERAPerMed program 'JAK- STAT-TARGET'. MLT was granted by SAF2016–75442-R (Agencia Estatal de Investigación/ European Regional Development Fund, European Union, Spain).