In vivo imaging of hematopoietic stem cells in the bone marrow niche.

Even though hematopoietic stem cells (HSC) are amongst the first somatic stem cells exploited for therapeutic purposes, their application is still limited by the inability to expand them ex vivo without impairing their function. Moreover, it has recently emerged that several types of leukemia develop and relapse through complex interactions with bone marrow (BM) components and may directly affect the HSC and their niche. Increasing attention has therefore been dedicated to the BM microenvironment the HSC reside in, with the view that a better understanding of the molecular regulators of HSC-niche interaction in vivo will allow improving HSC mobilization, collection and transplantation and provide clues for the development of innovative leukemia treatments.

Dormancy in the stem cell niche.

Tissues characterized by constant turnover contain post-mitotic, terminally differentiated cells originating from highly proliferative progenitors, which in turn derive from a relatively small population of stem cells. At the population level, self-renewal and differentiation are the possible outcomes of stem cell proliferation; overall, however, stem cells are quiescent if compared with their direct progeny. The recent discovery of a particularly quiescent, or dormant, subpopulation of hematopoietic stem cells (HSCs) raises a number of fundamental questions.

Dynamic expression of the p53 family members p63 and p73 in the mouse and human telencephalon during development and in adulthood.

p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and death of mammalian cells. They display high homology and may act in concert. The p73 gene is relevant for brain development, and p73-deficient mice display important malformations of the telencephalon.

ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development.

Cell polarity plays a key role in the development of the central nervous system (CNS). Interestingly, disruption of cell polarity is seen in many cancers. ASPP2 is a haplo-insufficient tumor suppressor and an activator of the p53 family.

Characterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase.

NPM/ALK is an oncogenic fusion protein expressed in approximately 50% of anaplastic large cell lymphoma cases. It derives from the t(2;5)(p23;q35) chromosomal translocation that fuses the catalytic domain of the tyrosine kinase, anaplastic lymphoma kinase (ALK), with the dimerization domain of the ubiquitously expressed nucleophosmin (NPM) protein. Dimerization of the ALK kinase domain leads to its autophosphorylation and constitutive activation.

Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling.

Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inhibition studies, and molecular modeling. Mutation of the gatekeeper residue, a key structural determinant influencing inhibitor binding, rendered the fusion protein, NPM/ALK, sensitive to inhibition by SKI-606 in the nanomolar range, while PD173955 inhibited the NPM/ALK mutant at micromolar concentrations.