Kevin Shannon, MD

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



Multidetector Computed Tomography Assessment of Anatomical Ventricular Tachycardia Isthmuses in Repaired Tetralogy of Fallot.

JACC. Clinical electrophysiology

Moore JP, Su J, Shannon KM, Perens GS, Newlon C, Bradfield JS, Shivkumar K

Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation.

JCI insight

Chen PY, Huang BJ, Harris M, Boone C, Wang W, Carias H, Mesiona B, Mavrici D, Kohler AC, Bollag G, Zhang C, Zhang Y, Shannon K

Opposing Effects of KDM6A and JDP2 on Glucocorticoid Sensitivity in T-ALL.

Blood advances

Levinson A, Tjoa K, Huang BJ, Meyer LK, Kim MO, Brady SW, Zhang J, Shannon KM, Wandler A

Precision Oncology for Papillary Craniopharyngioma.

The New England journal of medicine

Blakeley JO, Shannon K