Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.

• 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. MATERIALS AND 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. CONCLUSION: 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

Animals

Bone Marrow Transplantation

Cell Line

Tumor

Cell Transformation

Neoplastic

genetics

metabolism

Chemokine CCL3

biosynthesis

genetics

Disease Models

Animal

Gene Expression Profiling

Gene Expression Regulation

Leukemic

genetics

Genetic Complementation Test

Homeodomain Proteins

biosynthesis

genetics

Intracellular Signaling Peptides and Proteins

genetics

Leukemia

Myeloid

Acute

genetics

metabolism

Linkage (Genetics)

Mice

Neoplasm Proteins

biosynthesis

genetics

Oncogene Proteins

Fusion

genetics

metabolism

Protein Structure

Tertiary

genetics

Protein-Serine-Threonine Kinases

biosynthesis

genetics

Response Elements

genetics

Retroviridae

Structure-Activity Relationship

Transduction

Genetic

Publication and Content Type

ref (subject category)

art (subject category)