Kay L. Medina, Ph.D.

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SUMMARY

Kay L. Medina, Ph.D., studies B lymphocyte biology. B lymphocytes are a special category of white blood cells that produce antibodies to fight infection. Defects in B cell development or function can increase susceptibility to infection, cancer or autoimmune disease.

Dr. Medina's laboratory uses high-resolution multiparameter flow cytometry, mouse models, and short- and long-term culture models together with confocal and multidimensional microscopy techniques to study the generation and function of mouse and human B lymphocytes in health, aging and leukemogenesis.

Focus areas

• Defining the molecular and cellular mechanisms through which the transcription factor Hoxa9 regulates B lineage. Hoxa9 is expressed at high levels in primitive stem cells and plays a key role in the generation and maintenance of hematopoietic progenitors that give rise to B lymphocytes. Mice deficient in Hoxa9 have impaired lymphocyte development beginning in the stem cell compartment. Very little is known about the mechanisms by which Hoxa9 controls lymphoid lineage and B cell development, and these mechanisms have been a long-standing focus of Dr. Medina's research.
• The role of miR-204 in human pro-B acute lymphocytic leukemia (B-ALL). MicroRNA miR-204 is overexpressed in human ALLs. However, its role in ALL disease pathogenesis is unknown. In many cell types, MiR-204 has been implicated in the regulation of genes involved in maintenance of the undifferentiated state. Regulatory factors (including microRNAs) are key regulators of cell differentiation programs, and dysregulated function blocks cellular differentiation contributing to leukemic transformation. Dr. Medina's lab has determined that forced overexpression of miR-204 in mouse hematopoietic progenitors impairs their ability to undergo B cell differentiation in vitro and is pursing molecular mechanisms. The lab has also begun studying the role of miR-204 in human B-ALL through analysis of primary B-ALL cells isolated from diagnostic bone marrow samples. The goal is to determine if experimental ablation of miR-204 in human B-ALL represents a novel treatment for therapy-resistant leukemias.
• The impact of expanded clonal B cells on human bone marrow hematopoietic function, the innate immune repertoire and immune status. Accumulating data suggest that individuals with expanded B cell clonal populations have increased susceptibility to infections. Clonal B cells have been identified in the aged population, are a hallmark of individuals with monoclonal B cell lymphocytosis (MBL) and contribute significantly to the complex immunodeficiency well documented in patients with chronic lymphocytic leukemia (CLL). Dr. Medina's lab recently showed that patients with CLL have impaired bone marrow hematopoiesis and significant reductions in innate immune effector populations, providing new insight into their high propensity for infections. Studies are ongoing to determine the cellular and molecular mechanisms by which the CLL B-cell clone remodels the bone marrow microenvironment for its survival and escape from immune surveillance and therapy. The studies in CLL are being expanded to aged individuals and those with MBL who have varying levels of clonal B cells to determine if overabundance of clonal B cells impairs immune status.
• Understanding maintenance of the human bone marrow plasma cell niche. Long-lived plasma cells are terminally differentiated B lymphocytes that reside in the bone marrow in defined niches, where their sole function is to produce protective antibodies. While production of antibodies is critical for immune competence, some antibodies are pathogenic, contributing to autoimmunity or transplant rejection. Dr. Medina has developed an in vitro culture model that allows for the maintenance of long-lived plasma cells isolated directly from human bone marrow specimens. Her lab is using the culture model to identify and characterize critical components of the plasma cell niche to gain an understanding of the basis of the plasma cell deficiency in patients with CLL and to develop new targeting strategies to eradicate pathogenic plasma cells in various disease states.

Significance to patient care

The overall goals of Dr. Medina's research are to:

• Better understand mechanisms of B cell development to boost production of B cells in aged patients and after therapy-related ablation or stem cell transplantation
• Identify immune parameters that can be manipulated to maximize B cell vaccine responses
• Pinpoint genetic perturbations leading to immunodeficiencies