Profile

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

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

1. Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension. West J, Austin E, Fessel JP, Loyd J, Hamid R (2014) Drug Discov Today 19(8): 1241-5
   › Primary publication · 24794464 (PubMed) · PMC4396626 (PubMed Central)
2. Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension. Frump AL, Lowery JW, Hamid R, Austin ED, de Caestecker M (2013) PLoS One 8(11): e80319
   › Primary publication · 24224048 (PubMed) · PMC3818254 (PubMed Central)
3. SHC2 gene copy number in multiple system atrophy (MSA). Ferguson MC, Garland EM, Hedges L, Womack-Nunley B, Hamid R, Phillips JA, Shibao CA, Raj SR, Biaggioni I, Robertson D (2014) Clin Auton Res 24(1): 25-30
   › Primary publication · 24170347 (PubMed) · PMC3946192 (PubMed Central)
4. Tgif1 regulates quiescence and self-renewal of hematopoietic stem cells. Yan L, Womack B, Wotton D, Guo Y, Shyr Y, Davé U, Li C, Hiebert S, Brandt S, Hamid R (2013) Mol Cell Biol 33(24): 4824-33
   › Primary publication · 24100014 (PubMed) · PMC3889555 (PubMed Central)
5. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA, Hamid R, Loyd JE (2012) Am J Respir Crit Care Med 186(9): 892-6
   › Primary publication · 22923661 (PubMed) · PMC3530218 (PubMed Central)
6. Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. Cogan J, Austin E, Hedges L, Womack B, West J, Loyd J, Hamid R (2012) Circulation 126(15): 1907-16
   › Primary publication · 22923426 (PubMed) · PMC4113011 (PubMed Central)
7. Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming. Fessel JP, Hamid R, Wittmann BM, Robinson LJ, Blackwell T, Tada Y, Tanabe N, Tatsumi K, Hemnes AR, West JD (2012) Pulm Circ 2(2): 201-13
   › Primary publication · 22837861 (PubMed) · PMC3401874 (PubMed Central)
8. Pre-implantation genetic testing for hereditary pulmonary arterial hypertension: promise and caution. Hamid R, Loyd J (2012) Eur Respir J 39(6): 1292-3
   › Primary publication · 22654004 (PubMed)
9. High-altitude pulmonary hypertension in cattle (brisket disease): Candidate genes and gene expression profiling of peripheral blood mononuclear cells. Newman JH, Holt TN, Hedges LK, Womack B, Memon SS, Willers ED, Wheeler L, Phillips JA, Hamid R (2011) Pulm Circ 1(4): 462-9
   › Primary publication · 22530101 (PubMed) · PMC3329076 (PubMed Central)
10. The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress. Yan L, Guo S, Brault M, Harmon J, Robertson RP, Hamid R, Stein R, Yang E (2012) Biochem J 444(2): 239-47
    › Primary publication · 22417654 (PubMed) · PMC5006628 (PubMed Central)
11. BMPR2 expression is suppressed by signaling through the estrogen receptor. Austin ED, Hamid R, Hemnes AR, Loyd JE, Blackwell T, Yu C, Phillips Iii JA, Gaddipati R, Gladson S, Gu E, West J, Lane KB (2012) Biol Sex Differ 3(1): 6
    › Primary publication · 22348410 (PubMed) · PMC3310853 (PubMed Central)
12. Connectivity map analysis of nonsense-mediated decay-positive BMPR2-related hereditary pulmonary arterial hypertension provides insights into disease penetrance. Flynn C, Zheng S, Yan L, Hedges L, Womack B, Fessel J, Cogan J, Austin E, Loyd J, West J, Zhao Z, Hamid R (2012) Am J Respir Cell Mol Biol 47(1): 20-7
    › Primary publication · 22312021 (PubMed) · PMC3402799 (PubMed Central)
13. Idiopathic and heritable PAH perturb common molecular pathways, correlated with increased MSX1 expression. Austin ED, Menon S, Hemnes AR, Robinson LR, Talati M, Fox KL, Cogan JD, Hamid R, Hedges LK, Robbins I, Lane K, Newman JH, Loyd JE, West J (2011) Pulm Circ 1(3): 389-98
    › Primary publication · 22140629 (PubMed) · PMC3224431 (PubMed Central)
14. Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats. Stankiewicz P, Kulkarni S, Dharmadhikari AV, Sampath S, Bhatt SS, Shaikh TH, Xia Z, Pursley AN, Cooper ML, Shinawi M, Paciorkowski AR, Grange DK, Noetzel MJ, Saunders S, Simons P, Summar M, Lee B, Scaglia F, Fellmann F, Martinet D, Beckmann JS, Asamoah A, Platky K, Sparks S, Martin AS, Madan-Khetarpal S, Hoover J, Medne L, Bonnemann CG, Moeschler JB, Vallee SE, Parikh S, Irwin P, Dalzell VP, Smith WE, Banks VC, Flannery DB, Lovell CM, Bellus GA, Golden-Grant K, Gorski JL, Kussmann JL, McGregor TL, Hamid R, Pfotenhauer J, Ballif BC, Shaw CA, Kang SH, Bacino CA, Patel A, Rosenfeld JA, Cheung SW, Shaffer LG (2012) Hum Mutat 33(1): 165-79
    › Primary publication · 21948486 (PubMed) · PMC3655525 (PubMed Central)
15. A copy number variation morbidity map of developmental delay. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, Abdel-Hamid H, Bader P, McCracken E, Niyazov D, Leppig K, Thiese H, Hummel M, Alexander N, Gorski J, Kussmann J, Shashi V, Johnson K, Rehder C, Ballif BC, Shaffer LG, Eichler EE (2011) Nat Genet 43(9): 838-46
    › Primary publication · 21841781 (PubMed) · PMC3171215 (PubMed Central)
16. Pharmacologic correction of dominant-negative GH1 deficiency causing mutations. Poling JS, Phillips JA, Cogan JD, Hamid R (2011) Clin Transl Sci 4(3): 175-9
    › Primary publication · 21707947 (PubMed) · PMC5439858 (PubMed Central)
17. Somatic mutations in pulmonary arterial hypertension: primary or secondary events? Austin ED, Hamid R, Ahmad F (2010) Am J Respir Crit Care Med 182(9): 1094-6
    › Primary publication · 21041561 (PubMed)
18. Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension. Hamid R, Hedges LK, Austin E, Phillips JA, Loyd JE, Cogan JD (2010) Clin Genet 77(3): 280-6
    › Primary publication · 20095988 (PubMed) · PMC3741656 (PubMed Central)
19. A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II. Hamid R, Phillips JA, Holladay C, Cogan JD, Austin ED, Backeljauw PF, Travers SH, Patton JG (2009) J Clin Endocrinol Metab 94(12): 4728-34
    › Primary publication · 19837935 (PubMed) · PMC2795644 (PubMed Central)
20. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Austin ED, Phillips JA, Cogan JD, Hamid R, Yu C, Stanton KC, Phillips CA, Wheeler LA, Robbins IM, Newman JH, Loyd JE (2009) Respir Res : 87
    › Primary publication · 19785764 (PubMed) · PMC2762975 (PubMed Central)
21. Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells. Hamid R, Brandt SJ (2009) Mol Oncol 3(5-6): 451-63
    › Primary publication · 19699159 (PubMed) · PMC5527533 (PubMed Central)
22. Evidence for inflammatory signaling in idiopathic pulmonary artery hypertension: TRPC6 and nuclear factor-kappaB. Hamid R, Newman JH (2009) Circulation 119(17): 2297-8
    › Primary publication · 19414653 (PubMed)
23. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA (2009) Eur Respir J 34(5): 1093-9
    › Primary publication · 19357154 (PubMed) · PMC3742124 (PubMed Central)
24. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hamid R, Cogan JD, Hedges LK, Austin E, Phillips JA, Newman JH, Loyd JE (2009) Hum Mutat 30(4): 649-54
    › Primary publication · 19206171 (PubMed) · PMC2663001 (PubMed Central)
25. Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. Hamid R, Patterson J, Brandt SJ (2008) Biochim Biophys Acta 1779(5): 347-55
    › Primary publication · 18455519 (PubMed)
26. Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients. Lavin VA, Hamid R, Patterson J, Alford C, Ho R, Yang E (2008) Pediatr Blood Cancer 51(2): 298-302
    › Primary publication · 18454468 (PubMed)
27. Human mutations and their detection by gene and linkage analysis, allele sharing and association methods. Phillips JA, Hamid R (1999) East Mediterr Health J 5(6): 1140-6
    › Primary publication · 11924102 (PubMed)
28. Situs inversus with hypertrophic cardiomyopathy in identical twins. Agirbasli M, Hamid R, Jennings HS, Tiller GE (2000) Am J Med Genet 91(5): 327-30
    › Primary publication · 10766992 (PubMed)
29. Phenotypic determinants of adenovirus E1A gene autoregulation: variable region between conserved coding domains 2 and 3. Hamid R, Cogan JD, Jones SN, Tibbetts C (1995) Virology 213(2): 666-70
    › Primary publication · 7491791 (PubMed)

Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

Active Transport, Cell Nucleus Airway Remodeling Alternative Splicing Amino Acid Sequence Cell Line, Transformed Child, Preschool Cohort Studies Diseases in Twins Exons Family Health Gene Deletion Gene Dosage Gene Expression HeLa Cells Human Growth Hormone Hypertension, Pulmonary Infant Leukemia, Myeloid, Acute Lung Male Molecular Sequence Data Myelopoiesis Nonsense Mediated mRNA Decay Phosphorylation Pituitary Gland Protein Isoforms Receptors, Androgen Shc Signaling Adaptor Proteins TRPC6 Cation Channel Tubercidin