Page 383 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 26 Biology of Erythropoiesis, Erythroid Differentiation, and Maturation 319

are mainly satisfied through a greatly amplified late erythroid pool selective destruction at a given stage of maturation (of red cells only or
and with a minimum distortion in the differentiation sequence. 155,621 of both erythroblasts and red cells) can be observed depending on the
The fact that the kinetics of erythroid differentiation/maturation are type of antibody produced and the density of its antigen on maturing
different in acute versus chronic marrow regeneration is supported erythroid cells. Qualitative aberrations in the response of erythroid
by differing qualitative changes in the newly formed red cells. An progenitors to cytokines or EPO may underlie the abnormalities of
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increase in i antigen and HbF expression as well as an increase in cells congenital erythroid hypoplasia (Diamond-Blackfan syndrome).
with higher mean corpuscular volumes is seen with an acute response, Analogous qualitative or functional defects can be observed in neo-
whereas these alterations are minimal or less pronounced with chronic plastic erythropoiesis, because erythroid progenitors from patients
responses. 155,622 When severe anemia persists from birth onward, ery- with polycythemia vera and other myeloproliferative neoplasms have
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throid production can increase up to 10-fold above baseline. This altered sensitivities to EPO. 630
is possible not only because of maximally expanded erythropoietic Detailed knowledge of the structural and functional properties
pools but also because the sites of active erythropoiesis may extend of erythroid cells throughout their differentiation may provide
to include those that support red cell differentiation during fetal life. significant insights into the pathogenesis of hematopoietic disorders
Thus although the marrow space in axial bones (vertebrae, pelvis, affecting the red cell lineage.
ribs, sternum, clavicles) is sufficient for normal erythropoiesis or for
response to moderate anemia, the femur, humerus, spleen and/or liver,
and (rarely) thymus may support red cell production in children with SUGGESTED READINGS
congenital hemolytic anemia (e.g., thalassemia major). Expanded
erythropoiesis may lead to skeletal deformities, hepatosplenomegaly, Abdel-Wahab O, Levine R: The spliceosome as an indicted conspirator in
or erythropoiesis in the soft tissues adjacent to bone. myeloid malignancies. Cancer Cell 20:420, 2011.
Quantitative assessments of changes in erythroid progenitor Agarwal N, Gordeuk RV, Prchal JT: Genetic mechanisms underlying regula-
cell pools in response to EPO stimulation can be made through tion of hemoglobin mass. Adv Exp Med Biol 618:195, 2007.
cultures of bone marrow cells. Despite sampling errors, erythroid Andrews NC: Closing the iron gate. N Engl J Med 366:376, 2012.
cultures can provide rough estimates of relative progenitor abundance Anstee DJ: The relationship between blood groups and disease. Blood
within an aspirated marrow specimen and have shown consistent 115:4635, 2010.
increases in the frequency of CFU-E in proportion to the level of Baron MH, Isern J, Fraser ST: The embryonic origins of erythropoiesis in
EPO stimulation. 623,624 Conversely, with increases in the hematocrit mammals. Blood 119:4828, 2012.
or in polycythemic animals, a decrease in CFU-E frequency has Bauer DE, Kamran SC, Orkin SH: Reawakening fetal hemoglobin: prospects
been observed. 625,626 In contrast to CFU-E, the incidence of BFU-E for new therapies for the beta-globin disorders. Blood 120:2945, 2012.
was found to fluctuate less with either acute or chronic expansion of Bianco P: Bone and the hematopoietic niche: a tale of two stem cells. Blood
erythropoiesis, probably because a few BFU-E can generate several 117:5281, 2011.
thousand cells. Furthermore, BFU-E can increase their fraction in Bieker JJ: Putting a finger on the switch. Nat Genet 42:733, 2010.
cycle and thus increase the number of differentiated progeny without Bissels U, Bosio A, Wagner W: MicroRNAs are shaping the hematopoietic
a significant change in their total numbers. Most BFU-E detectable in landscape. Haematologica 97:160, 2012.
marrow or blood erythroid cultures probably represent a reservoir of Bowie MB, Kent DG, Copley MR, et al: Steel factor responsiveness regulates
progenitors not normally participating in day-to-day erythropoiesis. the high self-renewal phenotype of fetal hematopoietic stem cells. Blood
The parameters needed to maintain a healthy or appropriate BFU-E 109:5043, 2007.
pool in hematopoiesis are not defined. That hematopoietic expansion Bowman TV, Trompouki E, Zon LI: Linking hematopoietic regeneration to
is curtailed in mice with steel mutations and anemia develops in mice developmental signaling pathways: a story of BMP and Wnt. Cell Cycle
627
treated with anti-C-KIT antibody suggests that adequate levels of 11:424, 2012.
normal KL may be crucial for early erythropoietic expansion. 205 Bresnick EH, Lee HY, Fujiwara T, et al: GATA switches as developmental
The rate of red cell production can also be accurately evalu- drivers. J Biol Chem 285:31087, 2010.
ated by ferrokinetic studies (i.e., study of iron incorporation into Bunn HF: New agents that stimulate erythropoiesis. Blood 109:868, 2007.
developing red cells). In addition, a marrow scan, typically with Byon JC, Papayannopoulou T: MicroRNAs: allies or foes in erythropoiesis?
technetium Tc 99m, can document the extent of active erythro- J Cell Physiol 227:7, 2012.
poiesis. However, these approaches are seldom necessary in clinical Choesmel V, Bacqueville D, Rouquette J, et al: Impaired ribosome biogenesis
practice because estimates of erythropoiesis can be obtained from the in Diamond-Blackfan anemia. Blood 109:1275, 2007.
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reticulocyte index. First, the observed percentage of reticulocytes is Crispino JD, Weiss MJ: Erythro-megakaryocytic transcription factors associ-
normalized to the hematocrit to calculate the total marrow output of ated with hereditary anemia. Blood 123:3080, 2014.
reticulocytes. Alternatively, the absolute number of reticulocytes per Di Baldassarre A, Di Rico M, Di Noia A, et al: Protein kinase Calpha
microliter can be counted directly using fluorescent RNA labeling. is differentially activated during neonatal and adult erythropoiesis and
However, because younger reticulocytes are prematurely released into favors expression of a reporter gene under the control of the (A)gamma
the circulation under conditions of acute need, the total number of globin-promoter in cellular models of hemoglobin switching. J Cell
reticulocytes overestimates the true level of red cell production as Biochem 101:411, 2007.
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measured by iron kinetics. Therefore a second correction is made Dore LC, Crispino JD: Transcription factor networks in erythroid cell and
to account for the maturation of early circulating reticulocytes, or megakaryocyte development. Blood 118:231, 2011.
“shift” cells (polychromatophilic red cells), when present in the blood Fabriek BO, Polfliet MM, Vloet RP, et al: The macrophage CD163
smear. The resulting reticulocyte index gives excellent estimates of surface glycoprotein is an erythroblast adhesion receptor. Blood 109:5223,
effective red cell production. 2007.
Although the presence, density, or both of EPORs on developing Flygare J, Aspesi A, Bailey JC, et al: Human RPS19, the gene mutated in
erythroid cells determines the responses to EPO, other properties Diamond-Blackfan anemia, encodes a ribosomal protein required for the
(e.g., surface antigens on BFU-E versus CFU-E versus end-stage maturation of 40S ribosomal subunits. Blood 109:980, 2007.
red cells) may provide the basis for selective suppression of CFU-E Fraser ST, Isern J, Baron MH: Maturation and enucleation of primitive
versus BFU-E or selective immune destruction of red cells versus erythroblasts during mouse embryogenesis is accompanied by changes in
erythroblasts. For example, suppression of CFU-E or erythroblasts cell-surface antigen expression. Blood 109:343, 2007.
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can occur in acquired pure red cell aplasia or B19 parvovirus infec- Ganz T, Nemeth E: Iron metabolism: interactions with normal and disordered
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tion, respectively, whereas BFU-E in both these conditions remain erythropoiesis. Cold Spring Harb Perspect Med 2:a011668, 2012.
largely unperturbed. Thus the boundary from BFU-E to CFU-E and Ghinassi B, Sanchez M, Martelli F, et al: The hypomorphic Gata1low
erythroblast may be biologically important for the pathophysiology mutation alters the proliferation/differentiation potential of the common
of these disease states. Furthermore, in acquired hemolytic anemia, megakaryocytic-erythroid progenitor. Blood 109:1460, 2007.