casein-kinase-ii and Thymus-Neoplasms

A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2-4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference.

Topics: Animals; Antibodies, Neoplasm; Apoptosis; Casein Kinase II; Caspase 9; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hematopoiesis; Hyaluronan Receptors; Injections, Intravenous; Injections, Subcutaneous; Lymphoma; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Phosphorylation; Protein Phosphatase 2; T-Lymphocytes; Thymoma; Thymus Neoplasms

Activation of the basic helix-loop-helix (bHLH) gene TAL-1 (or SCL) is the most frequent gain-of-function mutation in pediatric T cell acute lymphoblastic leukemia (T-ALL). Similarly, mis-expression of tal-1 in the thymus of transgenic mice results in the development of clonal T cell lymphoblastic leukemia. To determine the mechanism(s) of tal-1-induced leukemogenesis, we created transgenic mice expressing a DNA binding mutant of tal-1. Surprisingly, these mice develop disease, demonstrating that the DNA binding properties of tal-1 are not required to induce leukemia/lymphoma in mice. However, wild type tal-1 and the DNA binding mutant both form stable complexes with E2A proteins. In addition, tal-1 stimulates differentiation of CD8-single positive thymocytes but inhibits the development of CD4-single positive cells: effects also observed in E2A-deficient mice. Our study suggests that the bHLH protein tal-1 contributes to leukemia by interfering with E2A protein function(s).

Topics: Adaptor Proteins, Signal Transducing; Adenovirus E2 Proteins; Animals; Basic Helix-Loop-Helix Transcription Factors; Casein Kinase II; CD4 Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Dimerization; Disease Models, Animal; DNA; DNA-Binding Proteins; Helix-Loop-Helix Motifs; Humans; Leukemia-Lymphoma, Adult T-Cell; LIM Domain Proteins; Lymphoma; Metalloproteins; Mice; Mice, Transgenic; Mutagenesis; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1; TCF Transcription Factors; Thymoma; Thymus Gland; Thymus Neoplasms; Transcription Factor 7-Like 1 Protein; Transcription Factors

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with many substrates, some of which are involved in cell cycle regulation. CK2 activity is elevated in human solid tumors and leukemia, and dysregulated expression of CK2 induces lymphoma in transgenic mice. Mice that are deficient in p53 also develop lymphomas, and p53 activity may be regulated by CK2 phosphorylation. Here we demonstrate that CK2alpha transgenic mice partially or completely deficient in p53 develop thymic lymphomas at a markedly accelerated rate when compared to p53-deficient mice lacking the transgene. Lymphomas originating from CK2alpha transgenic mice that are heterozygous for p53 generally lose the wild type p53 allele, indicating that loss of p53 is an important step in tumor progression. Moreover, though lymphomas occur as early as 3 weeks of age in the transgenic mice that are nullizygous for p53, they are still monoclonal, indicating that additional stochastic mutations are required for their development. These lymphomas express high levels of myc mRNA and frequently ectopically express Lmo-2, a transcription factor involved in human T cell acute lymphocytic leukemia. The p53-null CK2alpha transgenic lymphomas grow rapidly but are highly prone to apoptosis, suggesting that transformation occurs through synergistic dysregulation of cell cycle control induced by misexpression of CK2 and loss of function of p53.

Topics: Animals; Casein Kinase II; Gene Dosage; Immunophenotyping; Lymphoma, T-Cell; Mice; Mice, Transgenic; Mutagenesis; Protein Serine-Threonine Kinases; Thymus Gland; Thymus Neoplasms; Tumor Suppressor Protein p53

Ectopic activation of the TAL-1 gene in T lymphocytes occurs in the majority of cases of human T cell acute lymphoblastic leukemia (T-ALL), yet experiments to date have failed to demonstrate a direct transforming capability for tal-1. The tal-1 gene product is a serine phosphoprotein and basic helix-loop-helix (bHLH) transcription factor known to regulate embryonic hematopoiesis. We have established a transgenic mouse model in which tal-1 mis-expression in the thymus results in the development of clonal T cell lymphoblastic leukemia/lymphoma. Thus, overexpression of tal-1 alone can be transforming, verifying its pathogenic role in human T-ALL. In addition, leukemogenesis is accelerated dramatically by transgenic co-expression of tal-1 and the catalytic subunit of casein kinase IIalpha (CKIIalpha), a serine/threonine protein kinase known to modulate the activity of other bHLH transcription factors. Although tal-1 is a substrate for CKII, the synergy of the tal-1 and CKIIalpha transgenes appears to be indirect, perhaps mediated through the E protein heterodimeric partners of tal-1. These studies prove that dysregulated tal-1 is oncogenic, providing a direct molecular explanation for the malignancies associated with TAL-1 activation in human T-ALL.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Casein Kinase II; Disease Models, Animal; DNA-Binding Proteins; Humans; Immunophenotyping; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Transgenic; Oncogenes; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Messenger; RNA, Neoplasm; T-Cell Acute Lymphocytic Leukemia Protein 1; Thymoma; Thymus Gland; Thymus Neoplasms; Transcription Factors; Transgenes