Biological and Biomedical Science
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Alan B. Cantor

Department of Pediatrics
Children's Hospital
Karp Research Building, Room 07213
1 Blackfan Circle
Boston, MA 02115
Tel: (617) 919-2026
Fax: (617) 730-0222
Email: alan.cantor@childrens.harvard.edu

Web Page: The Cantor Lab Page
3 postdoctoral fellows, 1 research assistant

The hematopoietic system serves as a useful model for studies of cell fate determination and lineage plasticity.  Lineage-specific transcription factors play essential roles in this process by activating certain genes, while simultaneously repressing alternate lineage genes.  Yet, how these transcription factors carry out their distinct gene-context dependent activities remains unclear.  Importantly, transcription factors involved in normal hematopoiesis are also frequently mutated in leukemia and pre-leukemic conditions in humans.  Therefore, further understanding the dysregulation of these transcription factors should provide novel insights into the molecular pathogenesis of these cancers, and potentially new therapeutic strategies.  

Current emphasis in my lab is on the role of GATA, RUNX and ETS family transcription factors in normal megakaryopoiesis (production of platelets) and leukemia.  Acquired mutations that lead to exclusive production of a short isoform of the transcription factor GATA-1 (GATA-1s) cause a transient myeloproliferative disorder (production of too many white blood cells) in newborns with Down syndrome (DS-TMD).  This myeloproliferation spontaneously resolves over the first few months of life.  However, about 20-30% of these infants subsequently develop megakaryoblastic leukemia (DS-AMKL) within about 1-2 years.  Why these GATA-1 mutations are so strongly selected for in a Down syndrome (trisomy 21) genetic background (they are never found in non-DS individuals), what causes DS-TMD to spontaneously resolve, and what the additional genetic events that lead to DS-AMKL are all unknown.  Inherited mutations in the transcription factor RUNX-1, another key hematopoietic transcription factor, lead to low platelet number and a high incidence of myelodysplastic syndrome (a pre-leukemic condition) and leukemia.   My laboratory recently showed that GATA-1, RUNX-1 and the ETS family member FLI-1 participate in dynamic multiprotein complexes during hematopoietic development, and that some of these protein-protein interactions are modulated by protein phosphorylation events.  

We are currently taking three approaches to further understand the roles of transcription factors in normal hematopoiesis and leukemia. The first is a proteomic strategy involving the isolation and characterization of multiprotein complexes involving these factors.  This utilizes metabolic biotin tagging of these factors followed by streptavidin affinity purification and identification of associated proteins by mass spectrometry.  After validation of results, the functional significance of identified proteins is assessed by lentiviral shRNA gene silencing and conventional mouse genetic techniques.  The second approach utilizes genome-wide identification of target genes of these factors (and their cis-regulatory elements) by a ChIP-sequencing technique that utilizes the metabolic biotin tag.  Lastly, we have collected DNA from families with low platelets and leukemia predisposition, and are using genetic studies to identify novel genes involved in this disorder.

 

 

References:

 

  • Cantor AB, Iwasaki H, Arinobu Y, Moran TB, Shigematsu H, Sullivan MR, Akashi K, Orkin SH.  2008.  Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage.  J. Exp. Med., 205:611-624. PMC ID: PMC 2275384.
  • Woo A, Moran TB, Choe S-K, Schindler Y, Sullivan MR, Fujiwara Y, Paw BH, Cantor AB.  2008.  Identification of ZBP-89 as a Novel GATA-1 Associated Transcription Factor Involved in Megakaryocytic and Erythroid Development.  Mol. Cell. Bio. 28:2675-2689.  PMC ID: PMC2293107.
  • Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Handel BV, Mikkola, HKA, Hirshhorn JN, Cantor AB, Orkin SH. 2008. Human Fetal Hemoglobin Expression is Regulated by the Developmental Stage-specific Repressor BCL11A.  Science 322:1839-1842.
  • Huang H, Yu M, Akie TE, Moran TB, Woo AJ, Tu N, Waldon Z, Lin YY, Steen H, Cantor AB. 2009.   Differentiation-dependent Interactions between RUNX-1 and FLI-1 During Megakaryocyte Development.  Mol. Cell. Bio.  May 26 [Epub ahead of print].