Academic Background

Lucio Castilla received his B. S. from the University of Buenos Aires in 1988, and his Ph.D. from the University of Michigan in 1995. He was a postdoctoral fellow in the National Human Genome Research Institute, at the National Institutes of Health, from 1995 to 2000. He joined the University of Massachusetts Medical School, in the Program of Gene Function and Expression, as an Assistant Professor in 2000. He is the recipient of a Special Fellow Award from the Leukemia and Lymphoma Society (1999) and an AACR-Sidney Kimmel Symposium for Cancer Research Scholar Award (2002). Dr. Castilla is a Leukemia and Lymphoma Society Scholar (2007-2012).

Genetics of Leukemia, Mouse Models

The goal of our laboratory is to understand the molecular mechanisms of leukemia development. Leukemia arises from the abnormal expansion of hematopoietic stem cells that have acquired multiple genetic alterations that block differentiation programs and provide proliferation and survival capacity. The dimeric transcription factor “core-binding-factor” (CBF) is a master regulator of gene expression during development and differentiation. Genetic alterations in either CBF subunit, RUNX1 or CBFß, have been associated with human leukemia. For example, acute myeloid leukemia (AML) samples with chromosome 16 inversion express the fusion gene CBFB-MYH11. We and others have shown that Cbfb-MYH11 expression hinders multi-lineage differentiation. We have recently used a conditional Cbfb-MYH11 knock-in mouse model to show that the fusion gene also creates an abnormal myeloid progenitor that progress to AML upon the accumulation of cooperating mutations that provide proliferation and/or survival advantage (see Figure).

One line of our research uses conditional knock-in and knock-out strategies to better understand the role of CBF factors in hematopoietic stem cells and the alterations induced by Cbfb-MYH11 expression in this compartment as well as during multi-lineage differentiation. Second, we are characterizing the contribution of other de-regulated genes that collaborate with Cbfb-MYH11 in leukemogenesis. We use retroviral insertional mutagenesis in mice expressing Cbfb-MYH11 to identify candidate cooperating genes. We are particularly interested on one of these factors, the pleomorphic adenoma like-2 gene (PlagL2), and are studying its role in normal and malignant hematopoiesis. Third, the leukemic cells are a heterogeneous group of cells at different stages of differentiation. Few of these cells, called leukemia-initiating cells, hold the capacity to expand indefinitely and recreate the disease. We focus part of our efforts on characterizing the CBF leukemia-initiating cells, with the goal of identifying small molecules that inhibit Cbfb-MYH11 function and may be used in the design of improved therapy.

Potential Rotation Projects

1. Role of core binding factors on hematopoietic stem cell function and survival. We use molecular pharmacologic and functional approaches to study the role of the RUNX factors in self renewal and proliferation of hematopoietic stem and progenitor cells, using genetically modified mice and human progenitor cells.

2. Study the molecular mechanism of leukemia initiation and maintenance. Transcription factors and components of cytokine signaling are frequently mutated in human cancer, including leukemia. These mutations deregulate the proliferation, differentiation and survival of hematopoietic stem cells. We study the role of members of RUNX and RAS protein families in the function of hematopoietic stem cell function, pre-leukemic progenitors, and leukemia-initiating cells.

3. Translational research: Recent evidence suggests that inhibition of pathways activated by gene mutations can be used to eliminate leukemia cells, and not affecting normal cells. We use small molecule inhibitors of leukemia oncogenes to test whether repression of activated pathways hinder survival of leukemia initiating cells, and eliminate leukemia. We use a combination of mouse models and human leukemia cells to test the efficacy, specificity and toxicity of candidate inhibitors, as single agents or in combination with first line leukemia drugs.

The Castilla laboratory is accepting applications for postdoctoral positions. The candidates should be close to or have recently graduated with a Ph.D. or M.D./Ph.D. degree (within 1 year) in the fields of Cancer Biology, Genetics, Biochemistry, Cell Biology or related field. The candidates must also have a proven track record of productivity and research experience. Previous experience using immunocompromised and transgenic mice, in vitro and in vivo assays with small molecules or nanoparticles, or hematopoietic stem cells is preferred.

We are looking for highly motivated candidates with excellent communication skills, and able to work independently and in cooperation with other members of the laboratory.

Applicants should send their CV, a cover letter summarizing background and research interests, and three letters of references by electronic mail to: