Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic.

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions.

NK cells in the CD19- B220+ bone marrow fraction are increased in senescence and reduce E2A and surrogate light chain proteins in B cell precursors.

E2A encoded proteins, key transcriptional regulators in B lineage specification and commitment, have been shown to decrease in B cell precursors in old age. E2A regulates genes encoding the surrogate light chain proteins lambda5 and VpreB. In old age, B cell precursors express less surrogate light chain and this results in compromised pre-B cell receptor function and diminished expansion of new pre-B cells in senescence.

Accelerated Notch-dependent degradation of E47 proteins in aged B cell precursors is associated with increased ERK MAPK activation.

The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis. In BALB/c senescent mice (approximately 2 years old), the incidence of E47-expressing pro-B cells in vivo and E47 protein steady state levels in B cell precursors in vitro were reduced. Poor expression of E47 protein was a consequence of accelerated proteasome-mediated turnover and was associated with heightened ubiquitin modification of E2A-encoded proteins in aged B cell precursors.

CD28-mediated regulation of multiple myeloma cell proliferation and survival.

Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined.

Tumor necrosis factor-alpha triggers mucus production in airway epithelium through an IkappaB kinase beta-dependent mechanism.

Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IkappaB kinase beta (IKKbeta) in mucus synthesis in vitro and in vivo.

Caspase-9 and effector caspases have sequential and distinct effects on mitochondria.

Proapoptotic Bcl-2 family members alter mitochondrial permeability resulting in the release of apoptogenic factors that initiate a caspase cascade. These changes are well described; however, the effects of caspases on mitochondrial function are less well characterized. Here we describe the consequence of caspase-9 and effector caspase inhibition on mitochondrial physiology during intrinsic cell death.

Deficient B lymphopoiesis in murine senescence: potential roles for dysregulation of E2A, Pax-5, and STAT5.

B lymphopoiesis in senescent mice is typically diminished and characterized by low pre-B cell numbers. The transcription factors E2A, Pax-5, and STAT5 have been implicated in the differentiation, proliferation, and survival of B cell precursors. In this review, we discuss the impairment of B lymphopoiesis during old age in the context of mechanisms at the molecular level responsible for the handling and turnover of these key transcriptional proteins.

Pre-B cell loss in senescence coincides with preferential development of immature B cells characterized by partial activation and altered Vh repertoire.

Senescent mice show decline in B lymphopoiesis marked by reduced pre-B cells. Analysis of bone marrow from aged (approximately 2 years old) BALB/c mice indicates that, in senescence, an increased proportion of immature B cells exhibit a CD43/S7+ surface phenotype. This results from continued production of new CD43/S7+ B cells in aged mice from their limited pre-B cell pool while production of CD43/S7- immature B cells is highly reduced.

Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover.

The E2A-encoded transcription factor E47 is crucial to B lymphopoiesis. Senescent BALB/c mice ( approximately 2 years old) had reduced pre-B cells ex vivo. Pro-B/early pre-B cells from these aged mice, both ex vivo and in vitro, were deficient in E47 protein.

A phenotypically distinct subset of immature B cells exhibits partial activation, increased survival, and preferential expression of VhS107.

We have observed that immature B cells (IgM(low)IgD(-)) in the bone marrow of adult BALB/c mice exhibit heterogeneity, with a distinct subpopulation ( approximately 4-10%) expressing the CD43/S7 surface protein. These CD43/S7(+) immature B cells often express other surface antigens associated with B cell activation (CD5, CD11b, PD-1). Generation of optimal numbers of CD43/S7(+) immature B cells requires expression of a functional Btk protein, consistent with activation as a requisite for the CD43/S7(+) immature B cell phenotype.

Levels of E2A protein expression in B cell precursors are stage-dependent and inhibited by stem cell factor (c-kit ligand).

Objective: The E2A-encoded proteins E47 and E12 are crucial to the development of pro-B and pre-B cells. The expression of E2A protein and mRNA during early B lymphopoiesis was determined and effects of stem cell factor (SCF; Steel factor; c-kit ligand) on E2A expression were evaluated.

Materials And Methods: Ex vivo murine pro-B cells and pre-B cells were isolated and in vitro B cell precursors were derived after culture of bone marrow with rmIL-7.