Faculty Appointments
Professor of Pediatrics
Dorothy Overall Wells Chair in Pediatrics
Education
Ph.D., Microbiology & Immunology , Vanderbilt University, Nashville, TennesseeM.D., Allama Iqbal Medical College, Lahore, Pakistan
Office Address
DD-2205 MCN, Division of Medical Genetics
Department of Pediatrics
Vanderbilt University School of Medicine
Nashville, TN 37232
Department of Pediatrics
Vanderbilt University School of Medicine
Nashville, TN 37232
Research Description
Role of TGIF in Acute Myelogenous Leukemia (AML). We have discovered that quantitative expression of the stem cell expressed transcriptional repressor TGIF is the most discriminating and powerful predictor of patient survival identified in AML. Patients whose leukemic cells expressed decreased levels of TGIF RNA had a mean survival of 12 months, while patients whose leukemic cells expressed TGIF at a higher level had a mean survival of 60 months (p=0.00001).
Our data thus define a clinical role for TGIF as a prognostic indicator in AML, a role that has immediate clinical implications for AML treatment. Better risk stratification of AML patients, who prior to TGIF�s identification as a prognostic indicator did not have a usable prognostic indicator, will lead to better treatment decisions, with direct impact on morbidity and mortality. For example, in patients with high TGIF levels (expected to do well) stem cell transplant (SCT) would not be considered as an initial option, while in patients with low TGIF levels (expected to do worse), SCT would be an initial treatment option.
Our data also suggest a biological mechanism whereby TGIF affects AML prognosis. Our data show that Tgif may alter the exquisite balance between the key HSC functions of quiescence, self-renewal and differentiation. Regulation of these HSC functions is poorly understood and is frequently altered in acute leukemias; for example, increased quiescence in HSCs can make them more resistant to myelotoxic injury following chemotherapy, increasing the likelihood of relapse and/or poor long-term survival. Thus, elucidating the mechanisms through which Tgif alters HSC function will increase not only our understanding of HSC biology but also our comprehension of leukemia pathogenesis and treatment. Treatments that increase TGIF expression will make leukemic stem cells less quiescent and thus more likely to be affected by cytotoxic chemotherapy.
The research focus of this project is thus to
a) Understand and further define the cellular and molecular basis of Tgif�s role in normal and leukemic HSC function using mouse models.
b) Gain a better understanding of TGIF transcriptional pathway by identify downstream TGIF targets in HSC and use genetic and genomics approaches to identify genes and genomic regions that regulate TGIF expression.
c) Study the effects of single nucleotide polymorphisms (SNPs) on TGIF function and thus leukemic cell biology. There is a growing body of evidence that suggests that genetic factors play an important role in complex disease including cancer and that disease progression is determined by a complex interaction between somatic mutations and inherited traits. These inherited traits are usually SNPs or variants, and as opposed to a somatic mutation, these changes usually do not disrupt the gene function/expression but rather modify it. These variations would then impact the pathogenesis of a cancer by affecting its progression, metastasis, response to treatment and long-term survival. The role these common inherited variations play in leukemia biology has not been significantly explored. Our lab is in the process of addressing this important, but inadequately explored, aspect of leukemia pathogenesis.
Role of BMPR2 in Pulmonary Arterial Hypertension (PAH)
The long-term objectives of this project are to better understand the genetic factors that play a role in the pathogenesis of PAH and to use that information to improve disease diagnosis and therapy. More than 500,000 individuals are hospitalized annually in the United States with some form of PAH, and the mortality and morbidity increases each year. We have studied heritable (H) PAH, which is caused by mutations in the bone morphogenic protein-receptor-2 (BMPR2) gene, as a means to better understand the role of genetic risk factors involved in primary and secondary PAH.
Many key issues about HPAH remain unresolved, e.g., the mechanisms behind reduced penetrance, t
Our data thus define a clinical role for TGIF as a prognostic indicator in AML, a role that has immediate clinical implications for AML treatment. Better risk stratification of AML patients, who prior to TGIF�s identification as a prognostic indicator did not have a usable prognostic indicator, will lead to better treatment decisions, with direct impact on morbidity and mortality. For example, in patients with high TGIF levels (expected to do well) stem cell transplant (SCT) would not be considered as an initial option, while in patients with low TGIF levels (expected to do worse), SCT would be an initial treatment option.
Our data also suggest a biological mechanism whereby TGIF affects AML prognosis. Our data show that Tgif may alter the exquisite balance between the key HSC functions of quiescence, self-renewal and differentiation. Regulation of these HSC functions is poorly understood and is frequently altered in acute leukemias; for example, increased quiescence in HSCs can make them more resistant to myelotoxic injury following chemotherapy, increasing the likelihood of relapse and/or poor long-term survival. Thus, elucidating the mechanisms through which Tgif alters HSC function will increase not only our understanding of HSC biology but also our comprehension of leukemia pathogenesis and treatment. Treatments that increase TGIF expression will make leukemic stem cells less quiescent and thus more likely to be affected by cytotoxic chemotherapy.
The research focus of this project is thus to
a) Understand and further define the cellular and molecular basis of Tgif�s role in normal and leukemic HSC function using mouse models.
b) Gain a better understanding of TGIF transcriptional pathway by identify downstream TGIF targets in HSC and use genetic and genomics approaches to identify genes and genomic regions that regulate TGIF expression.
c) Study the effects of single nucleotide polymorphisms (SNPs) on TGIF function and thus leukemic cell biology. There is a growing body of evidence that suggests that genetic factors play an important role in complex disease including cancer and that disease progression is determined by a complex interaction between somatic mutations and inherited traits. These inherited traits are usually SNPs or variants, and as opposed to a somatic mutation, these changes usually do not disrupt the gene function/expression but rather modify it. These variations would then impact the pathogenesis of a cancer by affecting its progression, metastasis, response to treatment and long-term survival. The role these common inherited variations play in leukemia biology has not been significantly explored. Our lab is in the process of addressing this important, but inadequately explored, aspect of leukemia pathogenesis.
Role of BMPR2 in Pulmonary Arterial Hypertension (PAH)
The long-term objectives of this project are to better understand the genetic factors that play a role in the pathogenesis of PAH and to use that information to improve disease diagnosis and therapy. More than 500,000 individuals are hospitalized annually in the United States with some form of PAH, and the mortality and morbidity increases each year. We have studied heritable (H) PAH, which is caused by mutations in the bone morphogenic protein-receptor-2 (BMPR2) gene, as a means to better understand the role of genetic risk factors involved in primary and secondary PAH.
Many key issues about HPAH remain unresolved, e.g., the mechanisms behind reduced penetrance, t
Publications
Rizwan Hamid*, Julie Means*, Danko Martincic, Vladimir D. Kravtsov, Yu Shyr, John P. Greer, Daniel W. Byrne, Mark J. Koury, and Stephen J. Brandt. * Contributed equally. Quantitative expression of the TG-Interacting Factor gene in blast cells predicts clinical outcome in acute myeloid leukemia. In review. 2011.
John H. Newman, Rizwan Hamid, Christopher M. Seabury, Shafia S. Memon, MD2, Timothy N. Holt, James E. Womack, Elisabeth D. Willers, Lisa Wheeler, John A. Phillips III. Genetic Basis of High Altitude Pulmonary Hypertension in Cattle (Brisket Disease). In review. 2011.
Poling JS, Phillips Iii JA, Cogan JD, Hamid R.. Pharmacologic Correction of Dominant-Negative GH1 Deficiency Causing Mutations. Clinical and Translational Science. 2011; 4((3)): 175-9.
17 Eric D Austin,* Rizwan Hamid MD,* James E Loyd MD, Anna R Hemnes MD, Tom Blackwell, John A. Phillips III, Radhika Gaddipati, Santhi Gladson, James West, Kirk B Lane *Contributed equally. Estrogen-mediated suppression of BMPR2 expression: implications for PAH gender disparity. Biology of Sex Differences. 2011; In press.
Mehnaz Khan, Rizwan Hamid and Franco Recchia. Novel retinal findings in a child with muscle eye brain disease. Retina Cases and Case Reports. 2011; In press.
Gregory M. Cooper1, Bradley P. Coe, 5 others, Rizwan Hamid, Vickie Hannig, 21 others, Lisa G. Shaffer and Evan E. Eichler. A copy number variation morbidity map of developmental delay. Nature Genetics. 2011; In press.
Charles Flynn1, Siyuan Zheng4, Lora Hedges3, Bethany Womack3, Josh Fessel2, Joy Cogan3, Eric Austin3, James Loyd, James West2, Zhongming Zhao4, and Rizwan Hamid. Connectivity Map analysis of NMD+ BMPR2 related HPAH provides insights into disease penetrance. 2011; In review.
Ling Yan, Shuangli Guo, Marie Brault, Rizwan Hamid, Roland Stein, and Elizabeth Yang. PP2A/B55a regulates FOXO1 dephosphoralytion upon oxidative stress in pancreatic beta cells. 2011; In review.
Pawel Stankiewicz, Shashikant Kulkarni, 40 others, Samarth S. Bhatt, Rizwan Hamid, Jean Pfotenhauer, Blake C. Ballif, Sung-Hae L. Kang, Carlos A. Bacino, Ankita Patel. Recurrent deletions of 10q11.21q11.23 including CHAT are associated with complex low-copy repeats. Human Mutation. 2011; In press.
B.P. Concepcion, H. Bleibel, R. Hamid, and H.M. Schaefer. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome unmasked by kidney transplantation. 2011; In review.
John H. Newman MD, Timothy N. Holt DVM, Lora K. Hedges, Bethany Womack, James West PhD. Rizwan Hamid MD, PhD3,. Gene expression profiling of peripheral blood mononuclear cells from cattle with high altitude pulmonary hypertension (Brisket disease). 2011; In review.
R. Hamid, Lora K. Hedges, Eric Austin, John A Phillips III, James Loyd , Joy D. Cogan. Transcripts from a novel BMPR2 PTC mutation (W13X) escape NMD by downstream translation re-initiation, which can be reversed by treatment with gentamicin; implications for treating pulmonary hypertension. Clinical Genetics. 2010; 77((3)): 280-6.
Austin ED, Hamid R, Ahmad F.. Somatic mutations in pulmonary arterial hypertension: primary or secondary events. Am J Respir Crit Care Med. 2010; 182((9)): 1153-60.
Hamid R, Phillips JA, Holladay C, Cogan JD, Austin ED, Backeljauw PF, Travers SH, Patton JG. A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II. J. Clin. Endocrinol. Metab [print-electronic]. 2009 Dec; 94(12): 4728-34. PMID: 19837935, PMCID: PMC2795644, PII: jc.2009-0746, DOI: 10.1210/jc.2009-0746, ISSN: 1945-7197.
Hamid R, Brandt SJ. Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells. Mol Oncol [print-electronic]. 2009 Dec; 3(5-6): 451-63. PMID: 19699159, PII: S1574-7891(09)00087-8, DOI: 10.1016/j.molonc.2009.07.004, ISSN: 1878-0261.
Hamid R, Cogan JD, Hedges LK, Austin E, Phillips JA, Newman JH, Loyd JE. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum. Mutat. 2009 Apr; 30(4): 649-54. PMID: 19206171, PMCID: PMC2663001, DOI: 10.1002/humu.20922, ISSN: 1098-1004.
Austin ED, Phillips JA, Cogan JD, Hamid R, Yu C, Stanton KC, Phillips CA, Wheeler LA, Robbins IM, Newman JH, Loyd JE. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir. Res. 2009; 10: 87. PMID: 19785764, PMCID: PMC2762975, PII: 1465-9921-10-87, DOI: 10.1186/1465-9921-10-87, ISSN: 1465-993X.
Hamid R, Newman, J.. Evidence for Inflammatory Signaling in IPAH: TRPC6 and NFkB. Circulation. 2009; 17((119)): 2297-8.
Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA 3rd. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J. 2009; 5((34)): 1093-9.
Lavin VA, Hamid R, Patterson J, Alford C, Ho R, Yang E. Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients. Pediatr Blood Cancer. 2008 Aug; 51(2): 298-302. PMID: 18454468, DOI: 10.1002/pbc.21591, ISSN: 1545-5017.
Hamid R, Patterson J, Brandt SJ. Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. Biochim. Biophys. Acta [print-electronic]. 2008 May; 1779(5): 347-55. PMID: 18455519, PII: S1874-9399(08)00090-4, DOI: 10.1016/j.bbagrm.2008.04.003, ISSN: 0006-3002.
Kevin D. Hill, Rizwan Hamid, Vernat J. Exil. Pediatric cardiomyopathies related to fatty acid metabolism. Progress in Pediatric Cardiology. 2008; 2((51)): 69-78.
Tiller GE and Hamid R. Situs Inversus. The NORD Guide to Rare Disorders. 2003; 54-5.
Agirbasli M, Hamid R, Jennings HS, Tiller GE. Situs inversus with hypertrophic cardiomyopathy in identical twins. Am. J. Med. Genet. 2000 Apr 4/24/2000; 91(5): 327-30. PMID: 10766992, PII: 10.1002/(SICI)1096-8628(20000424)91:5<327::AID-AJMG1>3.0.CO;2-S, ISSN: 0148-7299.
Phillips JA, Hamid R. Human mutations and their detection by gene and linkage analysis, allele sharing and association methods. East. Mediterr. Health J. 1999 Nov; 5(6): 1140-6. PMID: 11924102, ISSN: 1020-3397.
Hamid R, Cogan JD, Jones SN, Tibbetts C. Phenotypic determinants of adenovirus E1A gene autoregulation: variable region between conserved coding domains 2 and 3. Virology. 1995 Nov 11/10/1995; 213(2): 666-70. PMID: 7491791, PII: S0042-6822(85)70039-6, DOI: 10.1006/viro.1995.0039, ISSN: 0042-6822.
Hamid, Rizwan. Auto-regulatory role of a non-conserved region of Human Adenovirus type 3 E1A gene. Thesis. 1994.
John H. Newman, Rizwan Hamid, Christopher M. Seabury, Shafia S. Memon, MD2, Timothy N. Holt, James E. Womack, Elisabeth D. Willers, Lisa Wheeler, John A. Phillips III. Genetic Basis of High Altitude Pulmonary Hypertension in Cattle (Brisket Disease). In review. 2011.
Poling JS, Phillips Iii JA, Cogan JD, Hamid R.. Pharmacologic Correction of Dominant-Negative GH1 Deficiency Causing Mutations. Clinical and Translational Science. 2011; 4((3)): 175-9.
17 Eric D Austin,* Rizwan Hamid MD,* James E Loyd MD, Anna R Hemnes MD, Tom Blackwell, John A. Phillips III, Radhika Gaddipati, Santhi Gladson, James West, Kirk B Lane *Contributed equally. Estrogen-mediated suppression of BMPR2 expression: implications for PAH gender disparity. Biology of Sex Differences. 2011; In press.
Mehnaz Khan, Rizwan Hamid and Franco Recchia. Novel retinal findings in a child with muscle eye brain disease. Retina Cases and Case Reports. 2011; In press.
Gregory M. Cooper1, Bradley P. Coe, 5 others, Rizwan Hamid, Vickie Hannig, 21 others, Lisa G. Shaffer and Evan E. Eichler. A copy number variation morbidity map of developmental delay. Nature Genetics. 2011; In press.
Charles Flynn1, Siyuan Zheng4, Lora Hedges3, Bethany Womack3, Josh Fessel2, Joy Cogan3, Eric Austin3, James Loyd, James West2, Zhongming Zhao4, and Rizwan Hamid. Connectivity Map analysis of NMD+ BMPR2 related HPAH provides insights into disease penetrance. 2011; In review.
Ling Yan, Shuangli Guo, Marie Brault, Rizwan Hamid, Roland Stein, and Elizabeth Yang. PP2A/B55a regulates FOXO1 dephosphoralytion upon oxidative stress in pancreatic beta cells. 2011; In review.
Pawel Stankiewicz, Shashikant Kulkarni, 40 others, Samarth S. Bhatt, Rizwan Hamid, Jean Pfotenhauer, Blake C. Ballif, Sung-Hae L. Kang, Carlos A. Bacino, Ankita Patel. Recurrent deletions of 10q11.21q11.23 including CHAT are associated with complex low-copy repeats. Human Mutation. 2011; In press.
B.P. Concepcion, H. Bleibel, R. Hamid, and H.M. Schaefer. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome unmasked by kidney transplantation. 2011; In review.
John H. Newman MD, Timothy N. Holt DVM, Lora K. Hedges, Bethany Womack, James West PhD. Rizwan Hamid MD, PhD3,. Gene expression profiling of peripheral blood mononuclear cells from cattle with high altitude pulmonary hypertension (Brisket disease). 2011; In review.
R. Hamid, Lora K. Hedges, Eric Austin, John A Phillips III, James Loyd , Joy D. Cogan. Transcripts from a novel BMPR2 PTC mutation (W13X) escape NMD by downstream translation re-initiation, which can be reversed by treatment with gentamicin; implications for treating pulmonary hypertension. Clinical Genetics. 2010; 77((3)): 280-6.
Austin ED, Hamid R, Ahmad F.. Somatic mutations in pulmonary arterial hypertension: primary or secondary events. Am J Respir Crit Care Med. 2010; 182((9)): 1153-60.
Hamid R, Phillips JA, Holladay C, Cogan JD, Austin ED, Backeljauw PF, Travers SH, Patton JG. A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II. J. Clin. Endocrinol. Metab [print-electronic]. 2009 Dec; 94(12): 4728-34. PMID: 19837935, PMCID: PMC2795644, PII: jc.2009-0746, DOI: 10.1210/jc.2009-0746, ISSN: 1945-7197.
Hamid R, Brandt SJ. Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells. Mol Oncol [print-electronic]. 2009 Dec; 3(5-6): 451-63. PMID: 19699159, PII: S1574-7891(09)00087-8, DOI: 10.1016/j.molonc.2009.07.004, ISSN: 1878-0261.
Hamid R, Cogan JD, Hedges LK, Austin E, Phillips JA, Newman JH, Loyd JE. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum. Mutat. 2009 Apr; 30(4): 649-54. PMID: 19206171, PMCID: PMC2663001, DOI: 10.1002/humu.20922, ISSN: 1098-1004.
Austin ED, Phillips JA, Cogan JD, Hamid R, Yu C, Stanton KC, Phillips CA, Wheeler LA, Robbins IM, Newman JH, Loyd JE. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir. Res. 2009; 10: 87. PMID: 19785764, PMCID: PMC2762975, PII: 1465-9921-10-87, DOI: 10.1186/1465-9921-10-87, ISSN: 1465-993X.
Hamid R, Newman, J.. Evidence for Inflammatory Signaling in IPAH: TRPC6 and NFkB. Circulation. 2009; 17((119)): 2297-8.
Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA 3rd. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J. 2009; 5((34)): 1093-9.
Lavin VA, Hamid R, Patterson J, Alford C, Ho R, Yang E. Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients. Pediatr Blood Cancer. 2008 Aug; 51(2): 298-302. PMID: 18454468, DOI: 10.1002/pbc.21591, ISSN: 1545-5017.
Hamid R, Patterson J, Brandt SJ. Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. Biochim. Biophys. Acta [print-electronic]. 2008 May; 1779(5): 347-55. PMID: 18455519, PII: S1874-9399(08)00090-4, DOI: 10.1016/j.bbagrm.2008.04.003, ISSN: 0006-3002.
Kevin D. Hill, Rizwan Hamid, Vernat J. Exil. Pediatric cardiomyopathies related to fatty acid metabolism. Progress in Pediatric Cardiology. 2008; 2((51)): 69-78.
Tiller GE and Hamid R. Situs Inversus. The NORD Guide to Rare Disorders. 2003; 54-5.
Agirbasli M, Hamid R, Jennings HS, Tiller GE. Situs inversus with hypertrophic cardiomyopathy in identical twins. Am. J. Med. Genet. 2000 Apr 4/24/2000; 91(5): 327-30. PMID: 10766992, PII: 10.1002/(SICI)1096-8628(20000424)91:5<327::AID-AJMG1>3.0.CO;2-S, ISSN: 0148-7299.
Phillips JA, Hamid R. Human mutations and their detection by gene and linkage analysis, allele sharing and association methods. East. Mediterr. Health J. 1999 Nov; 5(6): 1140-6. PMID: 11924102, ISSN: 1020-3397.
Hamid R, Cogan JD, Jones SN, Tibbetts C. Phenotypic determinants of adenovirus E1A gene autoregulation: variable region between conserved coding domains 2 and 3. Virology. 1995 Nov 11/10/1995; 213(2): 666-70. PMID: 7491791, PII: S0042-6822(85)70039-6, DOI: 10.1006/viro.1995.0039, ISSN: 0042-6822.
Hamid, Rizwan. Auto-regulatory role of a non-conserved region of Human Adenovirus type 3 E1A gene. Thesis. 1994.