title: Direct and indirect targeting of MYC to treat acute myeloid leukemia.
abstract: OBJECTIVE
  Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to examine the consequences of targeting MYC both directly and indirectly in AML overexpressing MYC/Myc due to trisomy 8/15 (human/mouse), FLT3-ITD mutation, or gene amplification.
  
  
  METHODS
  We performed in vivo knockdown of Myc (shRNAs) and both in vitro and in vivo experiments using four drugs with indirect anti-MYC activity: VX-680, GDC-0941, artemisinin, and JQ1.
  
  
  RESULTS
  shRNA knockdown of Myc in mice prolonged survival, regardless of the mechanism underlying MYC overexpression. VX-680, an aurora kinase inhibitor, demonstrated in vitro efficacy against human MYC-overexpressing AMLs regardless of the mechanism of MYC overexpression, but was weakest against a MYC-amplified cell line. GDC-0941, a PI3-kinase inhibitor, demonstrated efficacy against several MYC-overexpressing AMLs, although only in vitro. Artemisinin, an antimalarial, did not demonstrate consistent efficacy against any of the human AMLs tested. JQ1, a bromodomain and extra-terminal bromodomain inhibitor, demonstrated both in vitro and in vivo efficacy against several MYC-overexpressing AMLs. We also confirmed a decrease in MYC levels at growth inhibitory doses for JQ1, and importantly, sensitivity of AML cell lines to JQ1 appeared independent of the mechanism of MYC overexpression.
  
  
  CONCLUSIONS
  Our data support growing evidence that JQ1 and related compounds may have clinical efficacy in AML treatment regardless of the genetic abnormalities underlying MYC deregulation.
authors.affiliation: Department of Laboratory Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 513 Parnassus Avenue, Room S-561, Box 0451, San Francisco, CA, 94143-0451, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Brondfield
authors.forename: Sushma
authors.initials: S
authors.lastname: Umesh
authors.forename: Alexandra
authors.initials: A
authors.lastname: Corella
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Amy R
authors.initials: AR
authors.lastname: Rappaport
authors.forename: Coline
authors.initials: C
authors.lastname: Gaillard
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C489427:MYC protein, human; C489428:Myc protein, mouse; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines