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318 Part IV Disorders of Hematopoietic Cell Development

based on a proteomic approach that identified numerous proteins of mouse models of AML have identified GATA2 as one of the few
bound to RPS19. In addition to FGF2, complement component 5 key transcription factors whose expression is reduced in leukemic
receptor 1, a nucleolar protein called RPS19 binding protein, and blasts. 613
Pim-1, the other RPS19-binding proteins fall in the following Gene In conclusion, for a mechanism still to be identified, ribosomal
Ontology categories: NTPases (ATPases and GTPases; 5 proteins), deficiency may affect either GATA1 inducing DBA, or GATA2
hydrolases/helicases (19 proteins), isomerases (2 proteins), kinases inducing MDS deficiency. The different targets of the translational
(3 proteins), splicing factors (5 proteins), structural constituents of defect are reflected by the different agents that are effective in the
601
ribosome (29 proteins), transcription factors (11 proteins), trans- two diseases. DBA is treated with glucocorticoids that reduce
ferases (5 proteins), transporters (9 proteins), DNA/RNA-binding p53, reducing apoptosis, and increase BFU-E possibly by activat-
614
protein species (53 proteins), other (1 dehydrogenase protein, 1 ligase ing ZFP36L2, while MDS is treated with lenalinomide, which
615
protein, 1 peptidase protein, 1 receptor protein, 1 translation elonga- increases CFU-E possibly by activating Wnt/TGF-β signaling. 616
586
tion factor), and 13 proteins with unknown function. However,
more recent studies have identified that RPS19 plays an essential role
in the biogenesis and maturation of the 40S small ribosomal subunit CELLULAR DYNAMICS IN ERYTHROPOIESIS
in human cells 587,588 because of reduced gene expression of clustered
589
ribosomal proteins owing to abnormal pre-mRNA processing. The primary function of the mature red cell, which is the end
Such a defective ribosomal gene expression results in alterations of product of erythropoiesis, is to transport oxygen efficiently through
590
the transcription, translation, apoptosis, and oncogenic pathways. the circulation to the tissues. To achieve this goal, the adult marrow
9
Expression of RPS19 mRNA and protein decreases during terminal must release approximately 3 × 10 new red cells or reticulocytes per
591
617
erythroid differentiation. A mouse model of the disease has been kilogram per day. This number of reticulocytes represents (1%)
generated by disrupting the endogenous Rps19 gene. 592–594 Cellular of the total red cell mass and is derived from an estimated 5 ×
617
9
models of the disease have been established by small interfering RNA 10 erythroid precursors per kilogram. In addition to maintaining
(siRNA) technology against RPS19 protein. 595–597 These models are homeostasis (i.e., a stable hematocrit), the erythron must be able to
establishing that RPS19 deficiency is accompanied by an unantici- respond quickly and appropriately to increased oxygen demands,
pated activation of p53 and death of the erythroid cells. Treatment either acute (e.g., following red cell loss) or chronic (e.g., with
null
of RPS19 cells with dexamethasone prevents p53 activation and hypoxia from pulmonary disease or a right-to-left cardiac shunt). It is
598
restores terminal erythroid maturation, providing a molecular well established that EPO is responsible both for maintaining normal
mechanism for the therapeutic effects exerted by dexamethasone in erythropoiesis and for increasing red cell production in response to
these patients. Alternatively, it has been proposed that dexametha- oxygen needs. However, the overall marrow response is complex and
sone may rescue defective protein synthesis in ribosomal-deficient requires not only the participation of erythroid cells responsive to
erythroid cells by increasing expression of a subset of GR target genes EPO but also a structurally intact microenvironment and an optimal
(such as Zfp36l2, which controls RNA stability and/or translation iron supply within the marrow.
and is required for BFU-E self-renewal). 599,600 Only 40% to 50% EPO stimulation elicits two types of measurable responses:
601
of DBA patients respond to steroids. The mechanism underlying changes in proliferative activity (including improved survival) and
this lack of response has been the subject of recent investigation. The changes in maturation rates. The first detectable response to increased
increased frequency of rs6198 GR SNP observed in these patients serum EPO is amplification of CFU-E and erythroid precursors, cells
suggests that the failure to respond to steroids may be influenced by that are extremely sensitive to EPO. Because all these cells virtually
genetic and/or epigenetic modifications of the GR locus. are already in cycle, increases in their numbers cannot be achieved
In addition to ribosomal defects, DBA has been recently associ- by increasing their fraction in cycle. Either additional divisions are
ated with mutations in the GATA1 gene. 602,603 This discovery led to involved, or new cells are recruited to the CFU-E pool (from a
the identification that the ribosomal abnormalities observed in DBA pre–CFU-E pool). Additional divisions of CFU-E or precursor cells
reduces GATA1 translation. 604 would increase their transit time within the marrow and potentially
RSP19 deficiency and p53 activation is also observed in the delay the delivery of new red cells to the periphery. Because a short-
598
5q-MDS syndrome, and p53 activation associated with reduced ened maturation time has been observed instead and the proliferative
605
ribosomal gene dosage has been reported in low-risk MDS. Whole- potentials of CFU-E and proerythroblasts are finite, high levels of
exome sequencing of MDS has recently uncovered mutations in genes amplification cannot be achieved through this mechanism. Therefore
involved in RNA splicing. 606,607 Whether these mutations also activate such needs are met by influx into the CFU-E and precursor pools
p53 has yet to be determined. These results suggest that defective of newly differentiating cells from earlier progenitor compartments.
mRNA splicing/translation may represent a unifying mechanism for Such a surge of newly produced cells has been observed in prior
the etiology of MDS. Interestingly, MDS has also been associated experiments. 204,618,619 A rapid influx of fresh cells was particularly
with mutations in GATA2. In fact, in spite of its importance in notable in polycythemic mice that were experimentally depleted
the early phases of erythroid maturation, GATA2 mutations have of CFU-E and erythroid precursors at the time the stimulus was
not been detected in erythroid diseases so far. However, a gain-of- applied. 175,204 Because of the rapidity of response (i.e., within 24 hours
function GATA2 mutation has been reported in one patient with in the polycythemic animals), it appeared that the orderly progression
608
chronic myelomonocytic leukemia and loss-of-function GATA2 from BFU-E to CFU-E to proerythroblast had been compressed.
mutations have been systematically detected in patients with a rare Such acceleration of differentiation is possible through shortened
genetic immunodeficiency distinguished by reduced levels of all intermitotic intervals, fewer mitotic divisions, or differentiation
the immune cells produced in the marrow (monocytes, dendritic, without divisions. This short-circuiting in differentiation requires
NK and B cells, MonoMAC syndrome) 609,610 (see Table 26.2). The high serum levels of EPO and adequate numbers of BFU-E (i.e., these
marrow of these patients is hypocellular, with absent/reduced levels conditions are met in a previously hypertransfused, polycythemic
of multilymphoid and myeloid progenitor cells and dysplasia of the animal stimulated by EPO or in marrow suddenly recovering from
myeloid as well as the erythroid and megakaryocytic lineage. These acquired pure erythroid aplasia). Once CFU-E and precursors are
patients may eventually develop MDS and AML. Mutations in the expanded through this mechanism, most persisting erythropoietic
coding region of GATA2 have also been found in four patients with demands can be met through this pool without excess input from
611
MDS without immunodeficiency. In addition, quantitative altera- pre–CFU-E pools. Thus acute demand for erythropoiesis is met by
tions (reduced levels) in GATA2 expression, possibly secondary to the influx from pre–CFU-E pools through an accelerated differentiation
+
primary lesions, have been described in the CD34 cells from patients and maturation sequence. Demonstration of such an event was seen
612
613
with aplastic anemia and in blasts from AML, and although in mice with conditional deletions of integrins using the EPOR-Cre
620
hypomorphic GATA2 mutations do not induce a strong phenotype model deleting at the post–CFU-E level. In contrast, chronic
611
in mice, genome-wide analyses of transcriptional reprogramming demands (i.e., demands because of a chronic hemolytic anemia)