Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3.

• MEIS1 is a three-amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1 is rate-limiting in MLL-associated leukemias and potently interacts with Hox and NUP98-HOX genes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties. To further reveal the pathways triggered by Meis1, we assessed the function of a novel engineered fusion form of Meis1, M33-MEIS1, designed to confer transcriptional repression to Meis1 target genes that are otherwise up-regulated in normal and malignant hematopoiesis. Retroviral overexpression of M33-Meis1 resulted in the rapid and complete eradication of M33-Meis1-transduced normal and leukemic cells in vivo. Cell-cycle analysis showed that M33-Meis1 impeded the progression of cells from G(1)-to-S phase, which correlated with significant reduction of cyclin D3 levels and the inhibition of retinoblastoma (pRb) hyperphosphorylation. We identified cyclin D3 as a direct downstream target of MEIS1 and M33-MEIS1 and showed that the G(1)-phase accumulation and growth suppression induced by M33-Meis1 was partially relieved by overexpression of cyclin D3. This study provides strong evidence linking the growth-promoting activities of Meis1 to the cyclin D-pRb cell-cycle control pathway.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

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)

Nyckelord

Animals

Blotting

Western

Bone Marrow Transplantation

Cell Cycle

Cell Transformation

Neoplastic

Chromatin Immunoprecipitation

Cyclin D3

genetics

metabolism

Disease Models

Animal

Electrophoretic Mobility Shift Assay

Flow Cytometry

Gene Expression Profiling

Gene Expression Regulation

Leukemic

Hematopoiesis

Homeodomain Proteins

genetics

metabolism

Immunoprecipitation

Leukemia

Myeloid

Acute

genetics

metabolism

pathology

Luciferases

metabolism

Mice

Mice

Inbred C3H

Mice

Inbred C57BL

Neoplasm Proteins

genetics

metabolism

Oligonucleotide Array Sequence Analysis

Oncogene Proteins

Fusion

genetics

metabolism

RNA

Messenger

genetics

metabolism

Repressor Proteins

genetics

metabolism

Retinoblastoma Protein

genetics

metabolism

Retroviridae

genetics

Reverse Transcriptase Polymerase Chain Reaction

Transcriptional Activation

Transfection

Tumor Markers

Biological

genetics

metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)