Mark Willette

E-mail: wille173@umn.edu

Thesis Advisor: Mike Farrar

Year entered: 2005

Degrees received:
B.A., Biology Honors, Concordia College, Moorhead, MN 2003

Honors and awards:

• Immunology training grant 2008

Thesis research:
Pre-B cell acute lymphoblastic leukemia (pre-B ALL) is one of the most common forms of cancer in children, but factors that lead to its development have not been completely characterized. Limited studies have suggested that a percentage of patients with B ALL express activated STAT5. Recently, we found that mice expressing a constitutively active STAT5 transgene (STAT5b-CA) develop ALL, albeit with low penetrance (~1-2%). Other studies have suggested that loss of the adapter protein Blnk also contributes to the development of human ALL. Similarly, blnk-/- mice have an increased incidence of pre-B ALL (~5% penetrance). To examine potential cooperativity between STAT5b-CA and loss of Blnk, I generated STAT5b-CA x blnk+/- mice. I found that ~75% of STAT5b-CA x blnk+/- mice developed leukemia and that these leukemias shared features characteristic of human ALL. The transformed cells had also lost Blnk expression, and typically expressed high levels of the pre-BCR and interleukin-7 receptor. Subsequent studies demonstrated that crossing STAT5b-CA to mice lacking either the downstream Blnk effector Btk or PKC? resulted in an even greater penetrance of ALL (80-90%). Preliminary microarray studies on these tumors point to potential mechanisms that underlie transformation in these mice. My current model proposes that STAT5 activation coupled with loss function mutations in a coherent signaling pathway downstream of the pre-BCR initiates pre-B ALL. I aim to further develop this model by determining the mechanisms by which these pathways promote leukemia. These studies will give insight to how aberrations in distinct lymphocyte development signaling pathways cooperate to promote cancer, and thereby improve our understanding of onset, progression, and ultimately treatment of the disease.