Tcl1 and Mtcp1, members of the Tcl1 family, are implicated in T-cell prolymphocytic leukemia. The crystal structure of a dimer of murine Tcl1 has been determined at 2.5 A resolution with an R factor of 0.225. Murine Tcl1, human Tcl1 and Mtcp1 share very similar subunit structures, with RMS differences of 0.6 and 1.4 A for C(alpha) atoms, respectively, while the sequences share 50 and 36% identity, respectively. These structures fold into an eight-stranded beta-barrel of unique topology and high internal symmetry of 1.1-1.3 A for the two halves of human and murine Tcl1 and 1.7 A for Mtcp1, despite the low 12-13% sequence identity. The molecular surfaces of all three structures showed a common planar region which is likely to be involved in protein-protein interactions.
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http://dx.doi.org/10.1107/s090744490101352x | DOI Listing |
Hemasphere
December 2024
Department of Haemato-Oncology Comprehensive Cancer Centre, King's College London London UK.
Chronic lymphocytic leukemia (CLL) is an incurable progressive malignancy of CD5 B cells with a birth rate between 0.1% and 1% of the entire clone per day. However, the phenotype and functional characteristics of proliferating CLL cells remain incompletely understood.
View Article and Find Full Text PDFJ Exp Med
January 2025
Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany.
Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV.
View Article and Find Full Text PDFBlood Cancer J
August 2024
Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality.
View Article and Find Full Text PDFHaematologica
January 2025
Division of Hematopoietic Biology and Malignancy, MD Anderson Cancer Center, Houston TX.
Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax.
View Article and Find Full Text PDFInt J Mol Sci
June 2024
Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
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