Adam N. Goldfarb
- BA, Brown University, Providence, RI
- MD, Tufts University, Boston, MA
- Professor, Pathology
- Phone: 982-0593
- Email: email@example.com
Hematopathology and Understanding the Molecular Basis of Hematopoiesis and Leukemogenesis
The lab has two related areas of interest: 1) development of red cells and platelets within bone marrow precursors, and 2) the effects of iron deprivation on red cell and platelet development.
The platelet producing cells in the bone marrow, megakaryocytes, develop from a precursor cell that also gives rise to red blood cells. The genetic programming events that dictate the development of megakaryocytes along a pathway different from the red blood cells remain poorly understood. Nevertheless, these programming events are clearly disrupted in some types of human leukemia and in several human disorders of platelet production. Previous work in our lab has identified two proteins, RUNX1 and GATA-1, as key players in programming megakaryocyte development. These two proteins communicate with one another in this process using a novel signaling mechanism involving an enzyme known as Cdk9. Future experiments will provide a detailed understanding of how RUNX1, GATA-1, and Cdk9 cooperate in programming megakaryocyte development in mice and in human marrow cells. Importantly, several drugs currently in human trials are known to affect Cdk9 function and could profoundly influence megakaryocyte development.
Iron deficiency represents a frequent cause of anemia and causes the bone marrow to decrease production of red blood cells. In addition to iron deficiency anemia, anemias associated with cancer, kidney disease, chronic inflammation, and aging also are associated with impaired red cell production by the bone marrow. These latter anemias arise in part because of inadequate transport of iron from storage cells to the red cell precursors in the marrow. In particular, red cell precursors sense an iron deficiency even though total body iron stores are frequently increased.This project has identified the mechanisms by which bone marrow cells sense iron availability and adjust red cell production accordingly. Preliminary studies have led to compounds which can either reverse or mimic the response of marrow cells to diminished iron availability. These studies therefore offer novel approaches for the treatment of several types of chronic anemia and for the treatment of diseases associated with excessive red cell production such as polycythemia.
- Elagib K, Goldfarb A. Megakaryocytic irreversible P-TEFb activation. Cell cycle (Georgetown, Tex.). 2014;13(12): 1827-8. PMID: 24866976 | PMCID: PMC4111741
- Elagib K, Rubinstein J, Delehanty L, Ngoh V, Greer P, Li S, Lee J, Li Z, Orkin S, Mihaylov I, Goldfarb A. Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation. Developmental cell. 2013;27(6): 607-20. PMID: 24369834 | PMCID: PMC3892434
- Richardson C, Delehanty L, Bullock G, Rival C, Tung K, Kimpel D, Gardenghi S, Rivella S, Goldfarb A. Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response. The Journal of clinical investigation. 2013;123(8): 3614-23. PMID: 23863711 | PMCID: PMC3726169
- Rubinstein J, Elagib K, Goldfarb A. Cyclic AMP signaling inhibits megakaryocytic differentiation by targeting transcription factor 3 (E2A) cyclin-dependent kinase inhibitor 1A (CDKN1A) transcriptional axis. The Journal of biological chemistry. 2012;287(23): 19207-15. PMID: 22514271 | PMCID: PMC3365953
- Talbot A, Bullock G, Delehanty L, Sattler M, Zhao Z, Goldfarb A. Aconitase regulation of erythropoiesis correlates with a novel licensing function in erythropoietin-induced ERK signaling. PloS one. 2011;6(8): e23850. PMID: 21887333 | PMCID: PMC3161794
- Coordinating red cell differentiation with cell cycle arrest: GATA-1 activation of p21. Cell cycle (Georgetown, Tex.). 2010;9(11): 2061. PMID: 20559028
- Bullock G, Delehanty L, Talbot A, Gonias S, Tong W, Rouault T, Dewar B, Macdonald J, Chruma J, Goldfarb A. Iron control of erythroid development by a novel aconitase-associated regulatory pathway. Blood. 2010;116(1): 97-108. PMID: 20407036 | PMCID: PMC2904585
- Megakaryocytic programming by a transcriptional regulatory loop: A circle connecting RUNX1, GATA-1, and P-TEFb. Journal of cellular biochemistry. 2009;107(3): 377-82. PMID: 19350569 | PMCID: PMC2775554
- Yeh J, Munson K, Elagib K, Goldfarb A, Sweetser D, Peterson R. Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation. Nature chemical biology. 2009;5(4): 236-43. PMID: 19172146 | PMCID: PMC2658727
- Elagib K, Mihaylov I, Delehanty L, Bullock G, Ouma K, Caronia J, Gonias S, Goldfarb A. Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation. Blood. 2008;112(13): 4884-94. PMID: 18780834 | PMCID: PMC2597596
- Elagib K, Goldfarb A. Regulation of RUNX1 transcriptional function by GATA-1. Critical reviews in eukaryotic gene expression. 2007;17(4): 271-80. PMID: 17725493
- Choi Y, Elagib K, Delehanty L, Goldfarb A. Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1. Cancer research. 2006;66(6): 2990-6. PMID: 16540647