Martin H. Steinberg, MD

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PI: Martin H. Steinberg, M.D.

Title: Professor of Medicine

Center of Excellence in Sickle Cell Disease Boston Medical Center, Pediatrics, Pathology and Laboratory Medicine

Research interests: Sickle cell disease, inherited disorders of the erythrocyte

Clinical interests: Sickle cell disease, inherited disorders of the erythrocyte

 

Research Summary: The ability to genotype millions of polymorphisms in thousands of individuals and to sequence entire genomes affords the opportunity to understand how human diversity is associated with many diseases and longevity. It is also possible to direct the differentiation of patient-specific induced pluripotent stem cells, or iPSCs to erythroid progenitors that mature to produce hemoglobin. Both genomics and new iPSC technology can be used to study the molecular basis of phenotypic heterogeneity. This knowledge will then allow the development of predictive networks and genetic risk scores that can be used prognostically and point to functional studies of interesting variants and novel pathways that might can lead to new treatment options. We are taking this approach to the study of hemoglobin disorders focusing on sickle cell disease.

Fetal hemoglobin (HbF): HbF inhibits the polymerization of HbS and is therefore a key modulator of the phenotype of sickle cell anemia. Hydroxyurea can prevent some of the vasoocclusive complications of this disease, but not every patient responds to this treatment with a robust increase in HbF and the distribution of HbF among sickle erythrocytes is heterogeneous leading to some cells being unprotected from sickle polymer-induced damage.

The level of HbF and its cellular distribution varies among individuals, and this variation is likely to be a multigenic trait explained by genetic heterogeneity in: cis-acting elements and trans-acting factors modulating gamma-globin gene expression; genes or loci controlling erythroid cell differentiation and proliferation; genes or loci that directly or indirectly modulate HbF concentration. By studying special populations of patients with sickle cell anemia who have different haplotypes of the beta-globin gene cluster and widely different HbF levels and applying genomic and iPSC technology we hope to find novel modulators of HbF expression that can be prognostically useful, suggest new therapeutic approaches and uncover interesting new biology.

Associated Personnel:

Clinton Baldwin

Paola Sabastiani

Daniel Dworkis

Surinder Safaya

Alice Bisbee

Lindsay Farrer

David Chui

Hon Luo

Susan Perrine

Lillian McMahon

Philippa Sprinz

Elizabeth Klings

Publications:

Sebastiani, P., Wang, L., Nolan, V.G., Baldwin, C.T., Ma, Q., Steinberg, M.H. Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations. Am. J. Hematol. 83: 189, 2008.

Morris, C.R., Suh, J.H., Larkin, S., Bland, D.A., Steinberg, M.H.,Vichinsky, E.P., Shigenaga, M., Ames, B., Kuypers, F.A., Klings, E.S. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111: 402, 2008.

Sebastiani, P.,  Zhao, Z.,  Abad-Grau, M, Riva, A., Hartley, S., Sedgewick, A., Doria, A., Montano, M., Melista, E., Terry, D., Perls, T.T.,  Steinberg, M.H., Baldwin, C.T. A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples. BMC Genet.ePub  Jan 14, 2008.

Klings, E.S., Bland, A., Rosenman, D., Princeton, S., Odhiambo, A., Li, G., Bernard, S.A.,  Steinberg, M.H., Farber, H.W. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression Am. J.Hematol. 83: 547, 2008.

Taylor, J.G., IV, Nolan, V.G., Mendelsohn, L., Kato, G J., Gladwin, M.T., Steinberg, M.H. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One May 7;3(5):e2095, 2008.

Gibney, G.T., Panhuysen, C.I.M., So, J.C.C., Ma, E.S.K., Ha, S.Y., Li, C.K., Lee, A.C.W., Li, C.K., Yuen, H.L., Lau, Y.L., Johnson, D., Farrell, J.J., Bisbee, A., Farrer, J.J., Steinberg, M.H., Chan, L.C., Chui, D.H.K. Variation and heritability of Hb F and  F-cells among β-thalassemia heterozygotes in Hong  Kong. Am. J. Hematol. 83: 458, 2008.

Chen,Z., Hong-yuan, L,. Basran, R.K., Rosenfield, C.G., Patrinos, G.P., Hardison, R.C., Steinberg, M.H., Chui, D.H.K. A T-to-G  transversion  at nucleotide -567  upstream  of HBG2 in a GATA-1 binding  motif is associated  with  elevated hemoglobin F. Mol. Cell. Biol. 28: 4386,  2008.

Sedgewick, A.E., Timofeev, N., Sebastiani, P., So, J.C.C., Ma, E.S.K., Chan, L.C., Fucharoen, G., Fucharoen, S., Barbosa, C.G., Vardarajan, B., Farrer, L.A., Baldwin, C.T., Steinberg, M.H., Chui, D.H.K. BCL11A is  a major HbF  quantitative trait locus in three different  populations with β-hemoglobinopathies. Blood Cells, Mol. and Dis. 41: 255, 2008.

Nolan, V.G.,   Zhang, Y., Lash, T., Sebastiani, P., Steinberg,  M.H. Association of wind speed and the occurrence of sickle cell acute painful episodes: Results of a case-crossover study. Br. J. Haematol. 143: 433, 2008.

Zhao, Z.,  Timofeev, N., Hartley, S., Chui, D.H.K., Fuchareon,  Perls, T.T, Steinberg, M.H. Baldwin, C.T., Sebastiani, P. Imputation of missing genotypes: an empirical evaluation of IMPUTE. BMC Genetics (in press).

Taylor, J.G., IV, Nolan, V.G., Mendelsohn, L., Kato, G J., Gladwin, M.T., Steinberg, M.H. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One May 7;3(5):e2095, 2008.

Sedgewick, A.E., Timofeev, N., Sebastiani, P., So, J.C.C., Ma, E.S.K., Chan, L.C., Fucharoen, G., Fucharoen, S., Barbosa, C.G., Vardarajan, B., Farrer, L.A., Baldwin, C.T., Steinberg, M.H.,  Chui, D.H.K. BCL11A is  a major HbF  quantitative trait locus in three different  populations with β-hemoglobinopathies. Blood Cells Mol. and Dis. 41: 255, 2008.

Chen ,Z., Hong-yuan, L,. Basran, R.K., Rosenfield, C.G., Patrinos, G.P., Hardison, R.C., Steinberg, M.H., Chui, D.H.K. A T-to-G  transversion  at nucleotide -567  upstream  of HBG2 in a GATA-1 binding  motif is associated  with  elevated hemoglobin F. Mol. Cell. Biol. 28: 4386,  2008.

Steinberg, M.H., Forget, B.G., Higgs, D.R., Weatherall, D.J.  eds. Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, 2nd ed. Cambridge University Press, Cambridge, 2009, 826 pp.

Steinberg, M.H., Benz, E.J., Adewoye, H., Ebert, B.L. Chapter 33, Pathobiology of the Human Erythrocyte and its Hemoglobins.  Hematology. Basic Principles and Practice, 5th ed. Hoffman, R., Benz, E. J., Jr., Shattil, S.J., Furie, B., Cohen, H. J., Silberstein, L., McGlave, P., eds, Philadelphia, p 427-438, 2009.

Steinberg, M.H. Genetic etiologies for phenotypic diversity in sickle cell anemia.          TheScientificWorldJournal 9, 46, 2009.

Sebastiani, P., Timofeev, N., Dworkis, D.,Perls, T.T., Steinberg, M.H. Genome-wide association studies and the genetic dissection of complex traits. Am. J. Hematol. 84: 504, 2009.

Chui, D.H.K., Steinberg, M.H. Chapter 40. Laboratory Detection of Hemoglobinopathies and Thalassemias. Hematology. Basic Principles and Practice, 5th ed. Hoffman, R., Benz, E. J., Jr., Shattil, S.J., Furie, B., Cohen, H. J., Silberstein, L., McGlave, P., eds, Elsevier, Philadelphia, p 525-534, 2009

Solovieff, N., Milton, J.N., Hartley, S.W., Sherva, R., Sebastiani, P., Dworkis, D.A., Klings, E.S., Farrer, L.A., Garrett, M.E.,  Ashley-Koch, A., Telen, M.J., Fucharoen, S., Ha, S.Y., Li, C.K., Chui, D.H.K., Baldwin, C.T., Steinberg, M.H. Fetal hemoglobin in sickle cell anemia: Genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster. Blood 115: 1815, 2010.

Steinberg, M.H., McCarthy, W.F., Castro, O, Ballas, S.K., Armstrong, F.D., Smith, W., Ataga, K., Swerdlow, P., Kutlar, A., DeCastro, L., Waclawiw, M.A. The safety and effectiveness of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am. J. Hematol. 85: 403, 2010.

Verhovsek, M., Henderson, M.P.A., Cox, G., Luo, H.-y., Steinberg, M.H.,  Chui, D.H.K. Unexpectedly low pulse oximetry measurements associated with variant hemoglobins: a systematic review. Am. J. Hematol. 85: 882, 2010.

Steinberg, M.H. In the Clinic: Sickle cell disease. Ann. Intern. Med. 2011, Sep 6; 155(5) ITC31.

Wang, W., Brugnara, C.,Snyder, C., Wynn, L.,  Rogers, Z., Kalinyak, K., Brown, C. Qureshi, A., Bigelow, C.,  Neumayr, L., Smith-Whitley, K., Chui, D., Delahunty, M., Woolson, R., Steinberg, M.,  Telen, M., Kesler, K. The effects of hydroxycarbamide (hydroxyurea) and magnesium on haemoglobin SC disease:  Results of the multi-center CHAMPS trial. Br. J. Haematol. 152: 771, 2011.

Farrell, J.J., Sherva, R.M., Luo, H.-y., Chen, Z.-y., Ha, S.Y., Li, C.K., Lee, A.C.W., Li, C.K.,  Yuen, H.L.,  So, J.C.C., Ma, E.S.K., Chan, L.C.,  Chan, V. Sebastiani, P., Farrer, L.A., Baldwin, C.T.,  Steinberg, M.H., Chui, D.H.K.  A 3-bp deletion between transcription factor binding motifs in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with Hb F expression. Blood 117: 4935, 2011

Ngo, D.A.,  Aygun, B., Akinsheye, I., Hankins, J.S.,Bhan, I., Steinberg, M.H., Chui, D.H.K. Fetal haemoglobin levels and hematologic characteristics of compound heterozygotes for HbS and deletional hereditary persistence of fetal haemoglobin. Br. J. Haematol. 156: 259, 2011.

Steinberg, M.H. Sickle Cell Disease and Other Hemoglobinopathies, in, Cecil Medicine, Goldman and Ausiello, eds, Saunders/Elsevier, 24th ed., Chapter 166, 1066-1075, 2011.

Goldsmith, J.C., Noonan, A.S., Joiner, C.H., Bonham, V.L., Kato, G.J., Steinberg, M.H. Framing the research agenda for sickle cell trait: Building on the current understanding of clinical events and their potential implications. Am. J. Hematol. 87: 340, 2012.

Milton, J.N., Sebastiani, P., Solovieff, N., Hartley, S.W., Bhatnagar, P.,  Arking, D.E.,  Dworkis, D.A., Casella,  J.F., Barron-Casella, E.,  Bean, C.J., Hooper, W.C., DeBaun, M.R.,   Garrett, M.E., Soldano, K., Telen, M.J., Ashley-Koch, A., Gladwin, M.T., Baldwin, C.T.,  Steinberg M.H.,  Klings, E.S. A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia PlosOne 7(4):e34741. Epub 2012 Apr 27.

Bae, H., Baldwin, C.T., Steinberg, M.H., et al. Meta-analysis of 2040 sickle cell anemia patients confirms BCL11A and the  HBS1l-MYB intergenic interval as the major genetic modifiers of fetal hemoglobin in African Americans. Blood  120: 1961, 2012.

Primary teaching affiliate
of BU School of Medicine