Hematopoietic stem cells are maintained within a microenvironment where signals from a niche are important for the maintenance of quiescence within a precursor population. Lack of such a niche-derived signal will cause loss of "stemness" resulting in increased proliferation and eventual differentiation. We study this phenomenon in the Drosophila hematopoietic organ using genetic technologies available in this model organism (see Martinez-Agosto et al., Genes and Development, 2007 for a review).
We have shown that the "stemness" of these cells is maintained through the combined action of a Niche Signal, generated by Hedgehog (Hh) (Mandal et al., Nature, 2007), a local signal generated by Wingless/Wnt (Sinenko et al., Developmental Cell, 2009) and a reverse signal from the differentiated cells to the stem cells that we have termed the Equilibrium Signal. Several important concepts underlying Drosophila blood development have allowed us to propose this system as an appropriate genetic model for vertebrate hematopoiesis and these molecular mechanisms are being explored in the laboratory.
Myeloid blood cells are ideal for the study of response to many kinds of stresses. Hypoxia-related factors and free radicals known as reactive oxygen species (ROS) play a role both in hematopoietic development and in stress response (Owusu-Ansah and Banerjee, Nature 2009). Similarly, the NF-kB derived inflammatory response plays a major role in the way blood cells respond to injury at distant sites. The emerging view from these studies is that basic developmental mechanisms are co-opted again for stress, injury and inflammatory responses by the myeloid hematopoietic system. Genetic analysis allows us to understand the interrelationship between these important biological phenomena that have great relevance to diseases and disorders in humans.
In the past, our laboratory has identified components of signal transduction pathways that participate in oncogenesis (see Bonfini et al., Science, 1991; Flores et al., Cell 2000 for examples). We have also studied the role of the mitochondrion in controlling cell-cycle (Owusu-Ansah et al., Nature Genetics, 2008; Mandal et al., Developmental Cell, 2005). When cells become transformed, they choose alternate means of metabolism (a phenomenon referred to as the Warburg effect). We study the effect of signal transduction pathways on the control of cellular metabolism and the proper balance between cellular growth and metabolism that goes awry in cancer.