Page 428 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 28 Thrombocytopoiesis 349

FUTURE DIRECTIONS 12. Kaushansky K: The molecular mechanisms that control thrombopoiesis.
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Although the molecular details regarding the regulation and genera- 13. Gurney AL, Carver-Moore K, de Sauvage FJ, et al: Thrombocytopenia
tion of platelets remain to be fully elucidated, considerable progress in c-mpl-deficient mice. Science 265:1445, 1994.
has been made over the past few decades. This has been significantly 14. Bunting S, Widmer R, Lipari T, et al: Normal platelets and mega-
facilitated by the isolation of TPO and its receptor. Important models karyocytes are produced in vivo in the absence of thrombopoietin. Blood
of thrombocytopoiesis have now been tested rigorously in vivo, yield- 90:3423, 1997.
ing new insights into the final stages of platelet formation and 15. Bersenev A, Wu C, Balcerek J, et al: Lnk constrains myeloproliferative
shedding. These studies highlight the efficient mechanisms that have diseases in mice. J Clin Invest 120:2058, 2010.
developed to satisfy the demands for dynamic and high-output 16. Kimura S, Roberts AW, Metcalf D, et al: Hematopoietic stem cell
platelet production. Several important transcription factors have been deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin.
identified that regulate different stages of megakaryocytopoiesis, and Proc Natl Acad Sci USA 95:1195, 1998.
mutations in these, and other genes, have been linked to human 17. Nangalia J, Massie CE, Baxter EJ, et al: Somatic CALR mutations in
disorders of thrombocytopoiesis. The role of miRNAs in controlling myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med
thrombopoiesis is beginning to be appreciated. Although mouse 369:2391, 2013.
models have played important roles in the analysis of these genes, it 18. Grozovsky R, Begonja AJ, Liu K, et al: The Ashwell-Morell receptor
is becoming clear that they do not always faithfully recapitulate regulates hepatic thrombopoietin production via JAK2-STAT3 signaling.
human disease. In addition, several studies have documented impor- Nat Med 21:47, 2015.
tant differences between rodent and human platelets, including dif- 19. Olnes MJ, Scheinberg P, Calvo KR, et al: Eltrombopag and improved
ferences in size, circulating numbers, and DMS ultrastructural hematopoiesis in refractory aplastic anemia. N Engl J Med 367:11,
features. Thus some caution must be exercised when extrapolating 2012.
results of mouse studies to human thrombocytopoiesis. The advent 20. Ravid K, Lu J, Zimmet JM, et al: Roads to polyploidy: the megakaryo-
of megakaryocyte in vitro differentiation systems using human cyte example. J Cell Physiol 190:7, 2002.
+
CD34 cells, embryonic stem cells, and induced pluripotent cells are 21. Lordier L, Jalil A, Aurade F, et al: Megakaryocyte endomitosis is a failure
providing important tools for additional studies geared toward of late cytokinesis related to defects in the contractile ring and Rho/Rock
understanding and treating human disorders of megakaryocytopoiesis signaling. Blood 112:3164, 2008.
and thrombocytopoiesis. 22. Lordier L, Bluteau D, Jalil A, et al: RUNX1-induced silencing of
non-muscle myosin heavy chain IIB contributes to megakaryocyte
polyploidization. Nat Comm 3:717, 2012.
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