Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma.

Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4 T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL.

CK2β Regulates Hematopoietic Stem Cell Biology and Erythropoiesis.

The Ser-Thr kinase CK2 plays important roles in sustaining cell survival and resistance to stress and these functions are exploited by different types of blood tumors. Yet, the physiological involvement of CK2 in normal blood cell development is poorly known. Here, we discovered that the β regulatory subunit of CK2 is critical for normal hematopoiesis in the mouse.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas.

MYD88L265P augments proximal B-cell receptor signaling in large B-cell lymphomas via an interaction with DOCK8.

Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease with at least 5 recognized molecular subtypes. Cluster 5 (C5)/MCD tumors frequently exhibit concurrent alterations in the toll-like receptor (TLR) and B-cell receptor (BCR) pathway members, MYD88L265P and CD79B, and have a less favorable prognosis. In healthy B cells, the synergy between TLR and BCR signaling pathways integrates innate and adaptive immune responses and augments downstream NF-κB activation.

CK2β-regulated signaling controls B cell differentiation and function.

Serine-Threonine kinase CK2 supports malignant B-lymphocyte growth but its role in B-cell development and activation is largely unknown. Here, we describe the first B-cell specific knockout (KO) mouse model of the β regulatory subunit of CK2. CK2β mice present an increase in marginal zone (MZ) and a reduction in follicular B cells, suggesting a role for CK2 in the regulation of the B cell receptor (BCR) and NOTCH2 signaling pathways.

A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma.

PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined.

Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL.

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression.

The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma.

Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics.

CX-4945, a Selective Inhibitor of Casein Kinase 2, Synergizes with B Cell Receptor Signaling Inhibitors in Inducing Diffuse Large B Cell Lymphoma Cell Death.

Background: Approximately one third of Diffuse Large B cell Lymphomas (DLBCL) are refractory or relapse. Novel therapeutic approaches under scrutiny include inhibitors of B-cell receptor (BCR) signaling. Protein kinase CK2 propels survival, proliferation and stress response in solid and hematologic malignancies and promotes a "non-oncogene addiction" phenotype.

Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia.

Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory β subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis.

Targeting CK2-driven non-oncogene addiction in B-cell tumors.

Genetic mutations of oncogenes often underlie deranged cell growth and altered differentiation pathways leading to malignant transformation of B-lymphocytes. However, addiction to oncogenes is not the only drive to lymphoid tumor pathogenesis. Dependence on non-oncogenes, which act by propelling basic mechanisms of cell proliferation and survival, has also been recognized in the pathobiology of lymphoid leukemias, lymphomas and multiple myeloma.

Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed.

Guanylate cyclase activity in Escherichia coli mutants defective in adenylate cyclase.

Guanylate cyclase, which catalyzes the synthesis of guanosine 3',5'-monophosphate, has been assayed in several strains of Escherichia coli. They include wild-type cells and mutants defective in adenylate cyclase, which is responsible for the synthesis of adenosine 3',5'-phosphate. Our results demonstrate that adenylate cyclase and guanylate cyclase are two different enzymes in E.

Cyclic nucleotide metabolism in differentiated and undifferentiated epithelial thyroid cells in culture.

A highly differentiated thyroid cell line (FR-RL) was compared with a less differentiated (FR-T Cl1) and an undifferentiated (1-5G) cell line. FR-TL is modulated in vivo and in vitro by thyrotropin and has the lowest adenylate cyclase and guanylate cyclase and the highest phosphodiesterase activities. In contrast, 1-5G tumor cells do not respond to thyrotropin and have the highest adenylate cyclase guanylate cyclase and lowest hydrolyzing enzyme activities.

The adenylate cyclase-cyclic AMP-phosphodiesterase system in pathological human thyroid.

The adenylate cyclase-cyclic AMP-phosphodiesterase system of human thyroid tissues adjacent to cold nodules (control), two follicular adenomas, one hyperplastic thyroid and one hyperfunctioning follicular carcinoma have been compared. In the hyperfunctional follicular carcinoma the basal adenylate cyclase is much higher than in control tissue, carcinoma adenylate cyclase does not respond to TSH and prostaglandin E1, whereas it responds normally to fluoride. In the hyperplastic, but hypofunctional thyroid the basal adenylate cyclase is higher than in normal tissue whereas the response to TSH, PGE1, and fluoride is normal.

Diminished binding of thyroid-stimulating hormone in a transplantable rat thyroid tumor as a possible cause of hormone unresponsiveness.

The adenylate cyclase activity and the binding of 125I-labeled thyroid-stimulating hormone (TSH) of normal and tumor rat thyroid plasma membranes were compared. No significant difference in the basal and fluoride-sensitive adenylate cyclase activity between normal and tumor plasma membranes was observed. Thyroid plasma membranes responded to TSH, whereas the enzyme from the tumor plasma membranes was TSH insensitive.