Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

Journal name:
Pediatric Research
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Blood cell production or hematopoiesis is one of the most well-understood paradigms of cell differentiation in the body. The majority of work on hematopoiesis comes from studies that have primarily been conducted in mice, zebrafish, or other valuable model systems. However, it is clear that such model organisms may not consistently and faithfully mimic what is observed in humans with blood disorders. Moreover, there is significant divergence between species that is increasingly being appreciated at the genomic level. As a result, there is an opportunity to use observations in humans to provide a refined view of hematopoiesis. Here, we discuss vignettes from our work that illustrate how insight from human genetics can improve our understanding of blood cell production and identify promising therapeutic approaches for blood disorders.


  1. Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell 2012;10:12036.
  2. Sankaran VG, Weiss MJ. Anemia: progress in molecular mechanisms and therapies. Nat Med 2015;21:22130.
  3. Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 2008;132:63144.
  4. Busch K, Klapproth K, Barile M, et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 2015;518:5426.
  5. Sun J, Ramos A, Chapman B, et al. Clonal dynamics of native haematopoiesis. Nature 2014;514:3227.
  6. An X, Schulz VP, Li J, et al. Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood 2014;123:346677.
  7. An X, Schulz VP, Mohandas N, Gallagher PG. Human and murine erythropoiesis. Curr Opin Hematol 2015;22:20611.
  8. Pishesha N, Thiru P, Shi J, Eng JC, Sankaran VG, Lodish HF. Transcriptional divergence and conservation of human and mouse erythropoiesis. Proc Natl Acad Sci USA 2014;111:41038.
  9. Shay T, Jojic V, Zuk O, et al.; ImmGen Consortium. Conservation and divergence in the transcriptional programs of the human and mouse immune systems. Proc Natl Acad Sci USA 2013;110:294651.
  10. Ulirsch JC, Lacy JN, An X, Mohandas N, Mikkelsen TS, Sankaran VG. Altered chromatin occupancy of master regulators underlies evolutionary divergence in the transcriptional landscape of erythroid differentiation. PLoS Genet 2014;10:e1004890.
  11. Khoriaty R, Vasievich MP, Jones M, et al. Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B. Mol Cell Biol 2014;34:372134.
  12. Bianchi P, Fermo E, Vercellati C, et al. Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene. Hum Mutat 2009;30:12928.
  13. Schwarz K, Iolascon A, Verissimo F, et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nat Genet 2009;41:93640.
  14. Vlachos A, Blanc L, Lipton JM. Diamond Blackfan anemia: a model for the translational approach to understanding human disease. Expert Rev Hematol 2014;7:35972.
  15. Villar D, Flicek P, Odom DT. Evolution of transcription factor binding in metazoans - mechanisms and functional implications. Nat Rev Genet 2014;15:22133.
  16. Ott J, Wang J, Leal SM. Genetic linkage analysis in the age of whole-genome sequencing. Nat Rev Genet 2015;16:27584.
  17. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011;12:74555.
  18. Kiezun A, Garimella K, Do R, et al. Exome sequencing and the genetic basis of complex traits. Nat Genet 2012;44:62330.
  19. Sankaran VG, Gallagher PG. Applications of high-throughput DNA sequencing to benign hematology. Blood 2013;122:357582.
  20. Sankaran VG, Ghazvinian R, Do R, et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest 2012;122:243943.
  21. Ludwig LS, Gazda HT, Eng JC, et al. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med 2014;20:74853.
  22. Signer RA, Magee JA, Salic A, Morrison SJ. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 2014;509:4954.
  23. Iolascon A, Heimpel H, Wahlin A, Tamary H. Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood 2013;122:21626.
  24. Sankaran VG, Ulirsch JC, Tchaikovskii V, et al. X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation. J Clin Invest 2015;125:16659.
  25. Campagna DR, de Bie CI, Schmitz-Abe K, et al. X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations. Am J Hematol 2014;89:3159.
  26. Kaneko K, Furuyama K, Fujiwara T, et al. Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia. Haematologica 2014;99:25261.
  27. Manco L, Ribeiro ML, Máximo V, et al. A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency. Br J Haematol 2000;110:9937.
  28. Solis C, Aizencang GI, Astrin KH, Bishop DF, Desnick RJ. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. J Clin Invest 2001;107:75362.
  29. Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. J Clin Invest 2014;124:415461.
  30. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013;3:a011643.
  31. Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci USA 2008;105:16205.
  32. Lettre G, Sankaran VG, Bezerra MA, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci USA 2008;105:1186974.
  33. Menzel S, Garner C, Gut I, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet 2007;39:11979.
  34. Lander ES. Initial impact of the sequencing of the human genome. Nature 2011;470:18797.
  35. Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 2008;322:183942.
  36. Sankaran VG, Xu J, Ragoczy T, et al. Developmental and species-divergent globin switching are driven by BCL11A. Nature 2009;460:10937.
  37. Xu J, Sankaran VG, Ni M, et al. Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes Dev 2010;24:78398.
  38. Xu J, Bauer DE, Kerenyi MA, et al. Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci USA 2013;110:651823.
  39. Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 2013;342:2537.
  40. Basak A, Hancarova M, Ulirsch JC, et al. BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. J Clin Invest 2015;125:23638.
  41. Funnell AP, Prontera P, Ottaviani V, et al. 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood 2015;126:8993.
  42. Sankaran VG, Menne TF, Šćepanović D, et al. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proc Natl Acad Sci USA 2011;108:151924.
  43. Sankaran VG, Xu J, Byron R, et al. A functional element necessary for fetal hemoglobin silencing. N Engl J Med 2011;365:80714.
  44. Sankaran VG, Orkin SH. Genome-wide association studies of hematologic phenotypes: a window into human hematopoiesis. Curr Opin Genet Dev 2013;23:33944.
  45. Ludwig LS, Cho H, Wakabayashi A, et al. Genome-wide association study follow-up identifies cyclin A2 as a regulator of the transition through cytokinesis during terminal erythropoiesis. Am J Hematol 2015;90:38691.
  46. Sankaran VG, Ludwig LS, Sicinska E, et al. Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number. Genes Dev 2012;26:207587.
  47. van der Harst P, Zhang W, Mateo Leach I, et al. Seventy-five genetic loci influencing the human red blood cell. Nature 2012;492:36975.
  48. Migliaccio AR, Whitsett C, Papayannopoulou T, Sadelain M. The potential of stem cells as an in vitro source of red blood cells for transfusion. Cell Stem Cell 2012;10:1159.

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  1. Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

    • Aoi Wakabayashi &
    • Vijay G. Sankaran
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts

    • Aoi Wakabayashi &
    • Vijay G. Sankaran

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