Kevin Shannon, MD

Professor
Department of Pediatrics
Department of Cellular and Molecular Pharmacology
Research Overview: 

The Shannon Lab exploited inherited predispositions and recurring cytogenetic alterations as entry points to search for genetic lesions that contribute to leukemogenesis. This work has converged on the Ras signaling pathway and on the role of chromosome 7 deletions (monosomy 7) in leukemogenesis. We uncovered mutations in the NF1 and PTPN11 genes in juvenile myelomonocytic leukemia (JMML) and other myeloid malignancies. NF1, which encodes a GTPase activating protein for Ras, functions as a tumor suppressor gene. The PTPN11 and gene encodes SHP-2, a non-receptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to Ras and other effectors. Based on these human data, we harnessed the interferon-inducible Mx1-Cre recombinase to develop tractable mouse models of human myeloprolfierative neoplasms by inactivating Nf1 or by expressing oncogenic Nras and Kas in hematopoietic cells. To model more aggressive, multi-step human cancers, we performed retroviral insertional mutagenesis in Nf1, Nras, and Kras mutant mice to generate acute myeloid leukemia (AML and T lineage acute lymphoblastic leukemia (T-ALL). We extensively investigated inhibitor of MEK (PD0325901) and PI3 kinase (GDC-0941 in these models and have used them to elucidate mechanisms of response and resistance in vivo. We are also exploring novel strategies for selectively inhibiting the biochemical output of oncogenic N-Ras. The long-term goal of this research is to develop rational therapeutic strategies for preventing drug resistance and relapse in AML and other advanced hematologic cancers. We have also used chromosome engineering to model segmental deletions of chromosome band 7q22 found in myeloid malignancies and to interrogate how these alterations perturb hematopoiesis and contribute to leukemia.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Human Genetics
Research Summary: 
Aberrant Ras Signaling in Development and Cancer

Websites

Publications: 

ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth.

Nature chemical biology

Remsberg JR, Suciu RM, Zambetti NA, Hanigan TW, Firestone AJ, Inguva A, Long A, Ngo N, Lum KM, Henry CL, Richardson SK, Predovic M, Huang B, Dix MM, Howell AR, Niphakis MJ, Shannon K, Cravatt BF

KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice.

JCI insight

Wong JC, Perez-Mancera PA, Huang TQ, Kim J, Grego-Bessa J, Alzamora MDP, Kogan SC, Sharir A, Keefe SH, Morales CE, Schanze D, Castel P, Hirose K, Huang GN, Zenker M, Sheppard D, Klein O, Tuveson D, Braun BS, Shannon K

Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice.

Blood

Zambetti NA, Firestone AJ, Remsberg JR, Huang BJ, Wong JC, Long AM, Predovic M, Suciu RM, Inguva A, Kogan SC, Haigis KM, Cravatt BF, Shannon K

Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia.

Leukemia

Wandler AM, Huang BJ, Craig JW, Hayes K, Yan H, Meyer LK, Scacchetti A, Monsalve G, Dail M, Li Q, Wong JC, Weinberg O, Hasserjian RP, Kogan SC, Jonsson P, Yamamoto K, Sampath D, Nakitandwe J, Downing JR, Zhang J, Aster JC, Taylor BS, Shannon K