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
5 postdoctoral fellows, 1 undergraduate student, 1 research assistant

Multipotent progenitor cells give rise to progeny of two or more distinct phenotypes in many developmental settings. Yet the molecular mechanisms that determine these cell fate decisions remain incompletely understood. The hematopoietic system serves as a useful model for studying questions of cell fate determination and growth control. Prior work indicates that lineage-specific transcription factors play essential roles in this process. Importantly, a large number of these factors are also the target of mutations associated with various human leukemias and pre-leukemic conditions. Thus, the dysregulation of normal hematopoietic transcriptional machinery appears to play a role in the development of these malignancies.

My laboratory is focused on further elucidating the transcriptional mechanisms that regulate normal hematopoiesis, and how they may be perturbed in certain hematologic malignancies. Particular emphasis is on the role of GATA, FOG, RUNX and ETS transcription factor family members in megakaryocyte development. Recent work has shown that mutations leading to the generation of a tuncated isoform of GATA-1, a key transcription factor in megakaryopoiesis, are highly associated with a transient myeloproliferative disorder and megakaryoblastic leukemia in patients with Down syndrome. The mechanism for this remains unknown. RUNX-1, a hematopoietic transcription factor that is mutated in a large number of leukemias, has also recently been shown to play a specific role in megakaryocyte development. My laboratory has uncovered evidence that both GATA-1 and RUNX-1 participate in stable, large multiprotein complexes in megakaryocytic cells.

We are currently taking two approaches to further understand the roles of these two transcription factors in megakaryocyte development. The first is a proteomic strategy aimed at the isolation and characterization of stable multiprotein complexes involving these factors. This utilizes metabolic biotin tagging of these factors in hematopoietic cells, 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 RNAi gene silencing and zebrafish and mouse genetic techniques. The second approach is aimed at a genome-wide identification of target genes of these factors (and their cis-regulatory elements) by a chromatin immunoprecipitation-array hybridization technique “ChIP on Chip” and ChIP-solexa sequencing that takes advantage of the metabolic biotin tagging system.

References:

• Woo AJ, Moran TS, Schindler YS, Choe S-K, 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.

• 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.

• Cantor AB. 2005. GATA transcription factors in hematologic disease.  Int. J. Hemat. 81: 378-384.

• Pal S, Cantor AB, Johnson KD, Moran TB, Boyer ME, Orkin SH, Bresnick EH.  2004. Coregulator-dependent facilitation of chromatin occupancy by GATA-1.  Proc. Natl. Acad. Sci. USA, 101:980-5.