title: Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.
abstract: OBJECTIVE
  MEIS1, a HOX cofactor, collaborates with multiple HOX and NUP98-HOX fusion proteins to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms.
  
  
  METHODS
  To further resolve these mechanisms, we conducted a structure-function analysis of MEIS1 and gene-expression profiling, in the context of NUP98-HOXD13 (ND13) leukemogenesis.
  
  
  RESULTS
  We show, in a murine bone marrow transplantation model, that the PBX-interaction domain, the homeodomain, and the C-terminal domain of MEIS1, are all required for leukemogenic collaboration with ND13. In contrast, the N-terminal domain of MEIS1 is dispensable for collaboration with ND13, but is required for Flt3 upregulation, indicating additional roles for MEIS1 in induction of leukemia independent of alterations in Flt3 expression. Gene-expression profiling of a cloned ND13 preleukemic cell line transduced with wild-type or Meis1 mutant forms revealed deregulation of multiple genes, including a set not previously implicated as MEIS1 targets. Chromatin immunoprecipitation revealed the in vivo occupancy of MEIS1 on regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1. Furthermore, engineered overexpression of Trib2 complements ND13 to induce AML while Ccl3 potentiates the repopulating ability of ND13.
  
  
  CONCLUSIONS
  This study shows that Meis1-induced leukemogenesis with ND13 can occur in the absence of Flt3 upregulation and reveals the existence of other pathways activated by MEIS1 to promote leukemia.
authors: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors: Bob
authors: B
authors: Argiropoulos
authors: Lars
authors: L
authors: Palmqvist
authors: Eric
authors: E
authors: Yung
authors: Florian
authors: F
authors: Kuchenbauer
authors: Michael
authors: M
authors: Heuser
authors: Laura M
authors: LM
authors: Sly
authors: Adrian
authors: A
authors: Wan
authors: Gerald
authors: G
authors: Krystal
authors: R Keith
authors: RK
authors: Humphries
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D005816:Genetic Complementation Test; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000037:antagonists & inhibitors; D017434:Protein Structure, Tertiary / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D012190:Retroviridae; D013329:Structure-Activity Relationship; D014161:Transduction, Genetic
chemical_list: C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C515847:tribbles 2 protein, mouse; D017346:Protein Serine-Threonine Kinases