Project - Braun Lab

Ras Oncogenes in Leukemia Stem Cells

Ras mutations cooperate with a variety of other lesions to cause a fully transformed malignancy. However, oncogenic Ras has profound effects by itself on the biology of hematopoietic stem cells. Mice with the conditional knock-in Kras allele die from an aggressive ‘myeloproliferative disease,’ in which excessive production of mature and immature hematopoietic cells leads to death. Similar diseases in people are associated with RAS mutations. We have found that mutant Kras does not immortalize differentiated cells. By contrast, Kras mutant hematopoietic stem cells proliferate excessively and give rise to a durable and fatal disease. Our ongoing work aims to delineate the mechanism of cell cycle dysregulation in Kras mutant hematopoietic stem cells, and to better understand how Ras signaling influences stem cell fate. We are also using these mice to test signal transduction inhibitors as potential new therapies for leukemia.

Jon Akutagawa
SRA I
[email protected](415) 476-5060

SHP-2 Signaling in Leukemia:

Juvenile myelomonocytic leukemia (JMML) is an aggressive
myeloproliferative/myelodysplastic disorder marked by the clonal hyperproliferation of monocytes and granulocytes without differentiation arrest. Without treatment, the survival rate is roughly 5% and median survival is less than a year. In 2003, Tartaglia et al. reported that mutations in the gene PTPN11, which encodes the protein tyrosine phosphatase SHP2, accounts for 35% of sporadic cases of JMML. My goal is to use biochemical and molecular approaches to understand the role of SHP2 in JMML by identifying relevant protein binding partners and studying aberrant signaling downstream of the oncogenic mutant form of the protein

Danielle Shin
MD. Ph.D. Student
[email protected]
(415) 476-5060

Tannie Huang
Clinical Fellow
[email protected]
(415) 476-5060

Modeling Embryonal Rhabdomyosarcoma:

Embryonal rhabdomyosarcoma is an aggressive tumor of early childhood that arises in skeletal muscle. While often curable, survivors undergo intensive chemotherapy and endure tremendous morbidity from surgery and/or high dose radiation therapy. These tumors are genetically complex, but approximately 25% exhibit oncogenic Ras mutations (H- K- or N-Ras). Other common lesions include loss of imprinting at 11p15, p16INK4A/CDKN2A loss and p53 disruption. Some of these loci are also implicated by genetic syndromes associated with high rates of embryonal rhabdomyosarcoma: Costello syndrome (HRAS), Beckwith-Wiedemann syndrome (11p15), and Li-Fraumini syndrome (p53). We are building a murine model of embryonal rhabdomyosarcoma based on expression of oncogenic Ras in developing muscle to further investigate how oncogenes cooperate in this disease. We intend to use the experience we have gained through studying Ras in the hematopoietic system to effectively interrogate effects on biochemistry and cell fate imparted by mutant Ras in sarcoma.

Wan-Xing Hong
SRA I
[email protected]
(415) 476-5060