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Related Experiment Videos

Core-binding factor: a central player in hematopoiesis and leukemia.

N A Speck1, T Stacy, Q Wang

  • 1Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

Cancer Research
|April 10, 1999
PubMed
Summary

Chromosomal rearrangements in hematopoietic tumors disrupt core-binding factor (CBF) genes, essential for blood cell development. These disruptions create abnormal proteins that inhibit normal CBF function, impacting hematopoiesis.

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Area of Science:

  • Hematology
  • Molecular Biology
  • Genetics

Background:

  • Chromosomal rearrangements are common in hematopoietic tumors.
  • These rearrangements often disrupt genes critical for blood cell development.
  • Core-binding factors (CBFs) are transcription factors essential for hematopoiesis.

Purpose of the Study:

  • To investigate the role of core-binding factor (CBF) genes (CBFA2 and CBFB) in hematopoietic development and their disruption in tumors.
  • To understand how chromosomal rearrangements involving CBFA2 and CBFB lead to the formation of transdominant negative inhibitors.
  • To elucidate the impact of these disruptions on hematopoiesis at different developmental stages.

Main Methods:

  • Analysis of chromosomal rearrangements in hematopoietic tumors, specifically t(8;21), t(12;21), and inv(16).

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  • Identification of disrupted genes: CBFA2 (encoding CBFalpha) and CBFB (encoding CBFbeta).
  • Investigation of the functional consequences of chimeric proteins generated by these rearrangements.

    • Main Results:

    • Chromosomal rearrangements t(8;21) and t(12;21) disrupt the CBFA2 gene.
    • The inv(16) rearrangement disrupts the CBFB gene.
    • Both CBFA2 and CBFB are essential for definitive hematopoiesis in mice, required for hematopoietic stem cell emergence.
    • Transdominant negative inhibitors created by rearrangements can block hematopoietic cell emergence during embryogenesis.
    • Leukemic translocations involving CBFA2 and CBFB disrupt hematopoiesis at later stages than embryonic stem cell emergence.

    Conclusions:

    • Core-binding factor genes CBFA2 and CBFB are crucial for the earliest stages of definitive hematopoietic stem cell development.
    • Disruptions in CBFA2 and CBFB, leading to transdominant negative inhibitors, contribute to leukemogenesis by impairing hematopoiesis.
    • These genes are also required for later stages of hematopoietic lineage differentiation.