title: Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis.
abstract: RAS network activation is common in human cancers, and in acute myeloid leukemia (AML) this activation is achieved mainly through gain-of-function mutations in KRAS, NRAS or the receptor tyrosine kinase FLT3. We show that in mice, premalignant myeloid cells harboring a Kras(G12D) allele retained low levels of Ras signaling owing to negative feedback involving Spry4 that prevented transformation. In humans, SPRY4 is located on chromosome 5q, a region affected by large heterozygous deletions that are associated with aggressive disease in which gain-of-function mutations in the RAS pathway are rare. These 5q deletions often co-occur with chromosome 17 alterations involving the deletion of NF1 (another RAS negative regulator) and TP53. Accordingly, combined suppression of Spry4, Nf1 and p53 produces high levels of Ras signaling and drives AML in mice. Thus, SPRY4 is a tumor suppressor at 5q whose disruption contributes to a lethal AML subtype that appears to acquire RAS pathway activation through a loss of negative regulators.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. [2] Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Cory D
authors.initials: CD
authors.lastname: Rillahan
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kitzing
authors.affiliation: Department of Pathology, Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: McNerney
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Mona S
authors.initials: MS
authors.lastname: Spector
authors.affiliation: 1] Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Department of Laboratory Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. [2] Howard Hughes Medical Institute, New York, New York, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; C499037:Spry4 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
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