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Editorials
As another important consideration, individual Notch ligand/receptor pairs may have unique effects on hematopoietic function. Shao et al. focus on signaling through the Notch1 receptor, which is the predominant receptor expressed in endothelial cells. However, both Notch1 and Notch2 are present in HSPC, and a specific role for Notch2 in HSPC differentiation following bone marrow injury has been reported.3 Recent advances in the biophysics of Notch signaling could provide explanations as to how engagement of distinct receptor-ligand pairs can lead to divergent functions.20 Nandagopal et al. showed that Dll1/Notch1 signaling induced pulsatile Notch activation whereas Dll4/Notch1 signaling resulted in sustained Notch activation during myogenesis, allow- ing for ligand discrimination. Additional differences in the signaling potential of specific ligand-receptor pairs may also exist.21 Whether similar biophysical and func- tional differences apply to the effects of individual Notch receptors in hematopoietic progenitors remains to be investigated.
Altogether, Shao et al. provide compelling data indicat- ing that activation of Notch signaling between bone mar- row endothelial cells is necessary for niche regeneration, as well as efficient and timely hematopoietic recovery after bone marrow injury. With a panoply of Notch recep- tors and ligands expressed throughout the bone marrow, Notch has the potential to regulate a number of commu- nication channels between and among bone marrow cel- lular compartments. Future research should parse these cellular conversations to fully understand how Notch sig- naling helps to orchestrate hematopoiesis.
References
1. Crane GM, Jeffery E, Morrison SJ. Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017;17(9):573-590.
2. Poulos MG, Guo P, Kofler NM, et al. Endothelial Jagged-1 is neces- sary for homeostatic and regenerative hematopoiesis. Cell Rep. 2013;4(5):1022-1034.
3. Varnum-Finney B, Halasz LM, Sun M, Gridley T, Radtke F, Bernstein ID. Notch2 governs the rate of generation of mouse long- and short-
term repopulating stem cells. J Clin Invest. 2011;121(3):1207-1216. 4. Oh P, Lobry C, Gao J, et al. In vivo mapping of notch pathway activ- ity in normal and stress hematopoiesis. Cell Stem Cell.
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vironment at single-cell resolution. Nature. 2019;569(7755):222-228. 6. Butler JM, Nolan DJ, Vertes EL, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent
hematopoietic stem cells. Cell Stem Cell. 2010;6(3):251-264.
7. Klinakis A, Lobry C, Abdel-Wahab O, et al. A novel tumour-suppres- sor function for the Notch pathway in myeloid leukaemia. Nature.
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8. Maillard I, Koch U, Dumortier A, et al. Canonical notch signaling is
dispensable for the maintenance of adult hematopoietic stem cells.
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9. Duarte S, Woll PS, Buza-Vidas N, et al. Canonical Notch signaling is
dispensable for adult steady-state and stress myelo-erythropoiesis.
Blood. 2018;131(15):1712-1719.
10. Shao L, Sottoriva K, Palasiewicz K, et al. A Tie2-Notch1 signaling
axis regulates regeneration of the endothelial bone marrow niche.
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11. Kopan R, Ilagan MX. The canonical Notch signaling pathway:
unfolding the activation mechanism. Cell. 2009;137(2):216-233.
12. Yu VW, Saez B, Cook C, et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med.
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13. Guo P, Poulos MG, Palikuqi B, et al. Endothelial jagged-2 sustains
hematopoietic stem and progenitor reconstitution after myelosup-
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14. Lee SU, Maeda M, Ishikawa Y, et al. LRF-mediated Dll4 repression
in erythroblasts is necessary for hematopoietic stem cell mainte-
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Time for revival of the red blood cell count and red cell mass in the differential diagnosis between essential thrombocythemia and polycythemia vera?
Hans Carl Hasselbalch
Department of Hematology, Zealand University Hospital, Roskilde, Denmark E-mail: HANS CARL HASSELBALCH - hans.hasselbalch@gmail.com
doi:10.3324/haematol.2019.229039
Red blood cell indices, red blood cell mass and bone marrow biopsy in the differential diagnosis between essential thrombocythemia and polycythemia vera?
The correct diagnostic classification of the Philadelphia-negative chronic myeloproliferative neo- plasms (MPN) in the three subcategories, essential throm- bocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), relies upon diagnostic criteria that aim at minimizing misclassification.1 Several reports have addressed the issue that JAK2V617F positive “ET”
patients are frequently misclassified since they actually have a diagnosis of PV.2-8 This misclassification is partly based upon the use of the hemoglobin (Hb) concentration as a surrogate marker for the red cell mass (RCM), irre- spective of the fact that the Hb concentration is influ- enced by iron deficiency, which is prevalent in PV patients. Indeed, these concerns have been addressed and confirmed in several studies showing that a high propor- tion of ET patients (approx. 45-65%) did not meet the World Health Organization (WHO) diagnostic criterion
miR-155 in the bone marrow niche regulates hematopoiesis in an
NF-κB-dependent manner. Cell Stem Cell. 2014;15(1):51-65.
18. Himburg HA, Termini CM, Schlussel L, et al. Distinct bone marrow sources of pleiotrophin control hematopoietic stem cell maintenance
haematologica | 2019; 104(11)
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