Brain and CNS Infiltration by Acute Leukemia Cells: A Molecular Dissection

Iannis Aifantis, Ph.D.

New York University

Funded in September, 2008: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Determining How to Prevent Lymphoblastic Cancer Cells from Traveling to the Brain

Investigators will undertake laboratory studies to determine the molecular processes that lead cancerous white blood cells to infiltrate the brain in the disease called T cell acute lymphoblastic leukemia (T-ALL), in an effort to prevent the severe cognitive consequences of this cancer and enhance treatment in children and adolescents.

T-ALL is a blood cancer that primarily afflicts children and adolescents.  Cancerous “lymphocytic” white blood cells infiltrate the central nervous system (CNS, the brain, and spinal cord) at the diagnostic stage, and also—in about 30 percent of children and adolescents—following treatment, as the disease relapses in the brain and spinal cord.  Physicians aggressively use radiation therapy of the skull and chemotherapy, therefore, as a strategy to prevent CNS involvement initially and following treatment.  The strategy has improved outcomes, but at great cost.  Side-effects can include brain tumors, developmental delay, or mental retardation.  The frequency of these brain consequences has intensified efforts to identify the signaling pathways and genes responsible for leading the cancerous, lymphocytic white blood cells into the brain.

New York University investigators have identified a single gene that controls blood cell migration and adhesion (sticking together) and have determined that this gene is essential for enabling leukemia cells to invade the brain.  The gene produces a specific receptor for “chemokines,” proteins that prompt white blood cells to move.  In fact, when this single gene called “CCR7” is inactivated, leukemic white blood cells are unable to infiltrate the CNS.  Now the investigators will undertake laboratory studies in an animal model of T-ALL—including imaging and gene targeting techniques—and studies in patients’ cancer cells, to understand the molecular processes that the gene uses to lead leukemic blood cells into the CNS.

Significance: Understanding the molecular processes that the CCR7 gene uses to lead leukemic white blood cells into the CNS will be critical to determining how to block them and prevent CNS devastation from this cancer and its treatment.  

ABSTRACT

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Brain and CNS Infiltration by Acute Leukemia Cells: A Molecular Dissection

T cell acute lymphoblastic leukemia (T-ALL) is a common hematologic cancer that mainly afflicts children and adolescents. One of the most devastating features of the disease is tumor cell infiltration of the brain and the central nervous system either at the stage of the initial diagnosis or in patients with relapsed disease. It is thus a standard practice for all patients to receive prophylactic cranial irradiation and intrathecal chemotherapy. Although these protocols have resulted in improved treatment outcome, the side-effects for treated patients (especially children) can be devastating. It is thus very important to identify the signaling pathways and genes involved in brain infiltration and design specific and targeted therapies. The current application is based on preliminary observations that have identified a single adhesion mediator (the chemokine receptor CCR7), which normally controls lymphocyte cell migration and adhesion, as absolutely essential for the invasion of the brain by leukemia cells. Indeed, leukemic cells that lack CCR7 expression due to gene targeting are unable to infiltrate the CNS.

The main focus of our research proposal is the understanding the molecular mechanism(s) of CCR7 function in brain infiltration. To achieve our objectives we will use a combination of animal modeling of T-ALL, live animal imaging, gene targeting/ RNA-interference techniques and the study of primary T-ALL samples from patients with (or without) CNS infiltration. The impact of these studies for leukemia treatment and patient well-being will be very significant as if our preliminary observations are correct, targeting of a single surface reporter (using antibodies, RNAi or small molecules) could lead to total inhibition of leukemic CNS infiltration. It could also positively affect the lives of thousands of patients that could now avoid the devastating effects of high doses of cranial irradiation or chemotherapy.

INVESTIGATOR BIOGRAPHIES

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Iannis Aifantis, Ph.D.

Dr. Aifantis got his Ph.D. From the University of Paris V (René Descartes) and performed post-doctoral studies at Harvard Medical School and the Dana Farber Cancer Institute. Both graduate and post-graduate studies focused on the molecular mechanisms of blood cell development and function. He moved initially to the University of Chicago Medical School as an independent investigator and later to the NYU School of Medicine where he is now an Associate Professor and a Member of the NYU Cancer Institute.

His laboratory focuses on understanding and therapeutic targeting of leukemia, as well as on the identification of genes that are important for the differentiation and function of adult hematopoietic stem cells.