Chromosome 17p deletions are among the most frequent genetic abnormalities in various cancers and associated with a dismal prognosis. However, compared to comprehensive studies on individual gene mutations role in cancer biology, the impact of 17p deletions have long been simply considered as the inactivation of tumor suppressor gene TP53.Previous work in our laboratory identified additional tumor suppressor genes next to TP53, indicating that large deletions on 17p may contribute to cancer biology beyond their impact on eliminating wildtype TP53 allele. To explore this further, we generated a novel genetically-engineered mouse model that incorporates conditional deletion of chromosome 11B3, which is syntenic to the common deletion region on human 17p13.We found that besides p53, heterozygous deletion of linked genes on 11B3 not only promotes Myc-driven lymphomagenesis or Nf1; Mll3-defective leukemogenesis as seen by shorter tumor latency and overall survival than controls with only p53 loss, but also contributes to the poor outcome of chemotherapy treatments as shown by additional resistance to cyclophosphamide, vincristine and methotrexate. Furthermore, most lymphomas generated from heterozygous deletion of 11B3 have spontaneously missense or frame-shift mutations on the other wildtype p53 allele during the loss of p53 heterozygosity, which represents the major p53 configurations in human cancers. In contrast, no large deletion has been detected in lymphomas generated from current p53 mouse model with either deletion or mutation. Furthermore, to comprehensively understand the impact of individual 17p13 gene on tumorigenesis, we have performed a corresponding 17p13 shRNA library screening and identified several new tumor suppressors that is capable of promoting Em-Myc lymphoma development by its own or cooperating with p53 suppression in tumorigenesis. Moreover, three of them are clustered together, and all belong to arachidonate lipoxygenase (ALOX) family members, Alox15b-Alox12b-Aloxe3. Loss of Alox15b are found to be correlated with the cellular increase of its substrate, arachidonic acid, as measured by Lipid Chromatography-Mass Spectrometry (LC-MS).Additionally, in vitro extracellular arachidonic acid treatment suppresses the apoptosis of lymphoma-origin pre-B cells. Together, these results indicate that arachidonic acid metabolism pathway may contribute to the roles of 17p deletions in driving tumor. In summary, our results provide the new aspects of chromosome 17p deletions in cancer biology and may shed light on developing new therapeutic methods.