Page 381 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 26 Biology of Erythropoiesis, Erythroid Differentiation, and Maturation 317

570
adult life. The association between a mutation of GATA1 and the
by suppressing the biogenesis of the let-7 microRNA in adult CD34+ development of leukemia supports the concept that GATA1 controls
cells in vitro, upregulates HbF expression with production of fetal- the proliferation of hematopoietic progenitors. Reduced GATA1
like erythrocytes, thus presenting an additional target for increasing expression, by increasing progenitor cell proliferation, may predis-
fetal Hb to ameliorate beta globin disorders. 550,551 pose hematopoietic cells to leukemia by favoring accumulation of
secondary mutations. These mutations may involve the GATA1 itself
TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL because transforming Myb-GATA1 fusion genes have been associated
571,572
with reduced GATA1 levels in acute basophilic leukemia.
Altera-
IMPAIRMENT IN DISORDERS OF ERYTHROPOIESIS tions of hematopoietic proliferation appear to be achieved through
quantitative, rather than structural, GATA1 alterations. The GATA1s
The transcription factor found most frequently altered in inherited protein is far less efficient than the full-length GATA1 in rescuing the
489
null
and acquired human diseases of the erythroid and megakaryocytic phenotype of GATA1 embryonic stem cells, and hypomorphic
573
lineage is GATA1. The mutations often involve the region of the mutations in mice induce either leukemia or a phenotype similar
574
gene encoding the NF domain. Mutations in the GATA1 NF domain to idiopathic myelofibrosis, depending on the severity of the reduc-
interrupting its interaction with FOG-1, such as V205M and G208S, tion of expression. Interestingly, the reduced content of GATA1
are responsible for familial dyserythropoietic anemia and X-linked in megakaryocytes, through an as yet unidentified molecular defect
thrombocytopenia, respectively. 552,553 A different mutation at position independent of JAK2V617F, distinguishes primary myelofibrosis
575
208 leading to G→A substitution is associated with dyserythropoi- from all the other myeloproliferative neoplasms in humans. (For
554
etic anemia and macrothrombocytopenia. Mutations in the NF a more complete review on the role of GATA factors in hematologic
576
terminal domain of GATA1 responsible for DNA binding, such as diseases, see review article by Cantor .)
556
555
A216G and D218G, instead have been found to be associated Point mutations in the EKLF/KLF1 gene have been associated
with X-linked thalassemia and/or thrombocytopenia. The phenotype with human diseases of terminal erythroid maturation (see Table
of X-linked thrombocytopenia was mimicked in mice by knock-in 26.2). E325K substitution in the conserved residue of the zinc finger
557
experiments of the mutant V205G GATA1 gene. However, the domain 2 is associated with congenital dyserythropoietic anemia
same A216G mutation has been found associated with X-linked and increased levels of embryonic globins, revealing a role of EKLF
gray platelet syndrome, a mild bleeding disorder characterized by in repressing embryonic globin expression in humans. 577–579 Prema-
558
thrombocytopenia and large agranular platelet, whereas a R216G ture stop codons (L127X, K292X), point mutations in conserved
mutation was identified in two families in which the X-linked residues of the zinc finger 1 (H299Y) and 2 (R328L, R328H,
thrombocytopenia and thalassemia phenotype was associated with R331G), frameshift (X47 and X34), and hypomorphic mutations
559
a PMF phenotype (reticulin fibrosis and increased angiogenesis). (deletion of the GATA1 binding site in the promoter region) have
Furthermore, a mutation at codon 216 changing arginine to tryp- been associated with lack of Lutheran group antigen (Lu negative
580
tophan (R216W) was detected in a 3-year-old boy with congenital phenotype), whereas neutral substitution (M39L), premature stop
erythropoietic porphyria, an autosomal recessive disorder usually codon (K288X), and premature stop codon plus point mutations
because of mutations of the uroporphyrinogen III synthase gene in the conserved residue of zinc finger 2 (S270X plus K332Q) have
(UROS). The boy also presented with microcytic anemia and red been associated with the HPFH phenotype with or without elevated
cell morphologic characteristics and a globin chain pattern compat- zinc protoporphyrin. 455,457 Not all heterozygotes for EKLF mutations
560
ible with β-thalassemia and increased HbF levels (59.5%). The have increased HbF, and different levels are seen even with the same
different phenotype expressed by patients carrying mutations either mutation. Hereditary spherocytosis has also been observed in mice
in the FOG-1 or the DNA binding portion of NF supported the carrying the spontaneous Nan mutation (E339D substitution in the
notion that the two domains influence erythroid versus megakaryo- conserved residue of zinc finger 2). 581
561
cytic maturation. To clarify why mutations in the same codon Another disease associated with abnormalities in the molecular
may cause diseases with different phenotype, systematic analyses of machinery of red cell differentiation is represented by DBA, a rare
disease-causing GATA1 mutations in murine gene complementation congenital red cell hypoplasia characterized by anemia, bone marrow
562
systems were performed. These analyses revealed that mutations erythroblastopenia (lack of late erythroid forms), and congenital
shown to impair DNA binding of GATA1 in vitro did not affect anomalies. The disease is associated with heterozygous mutations in
target gene occupancy in vivo but rather disrupted GATA1 associa- the ribosomal protein S19 gene (RPS19) in approximately 25% of
582
tion with partner proteins. More specifically, substitution at the same probands. In a large cohort of 172 new families with familial history
amino acid selectively inhibited TAL1 or FOG1 binding, producing of DBA, mutations affecting the coding sequence of RPS19 or splice
distinct cell phenotype. However, this brilliant approach does not sites were found in 34 cases (19.8%), whereas additional mutations
explain why the same mutation results in a different phenotype. It in noncoding regions were found in eight patients (4.6%). Mutations
is possible that the phenotype induced by mutations in the GATA1 included nonsense, missense, splice site, and frameshift mutations.
gene is extremely sensitive to genetic modifiers outside the GATA1 More recently, de novo nonsense and splice-site mutations in another
locus. This hypothesis has been demonstrated in mice in which the ribosomal protein, RPS24 (encoded by RPS24 [10q22-q23]), was
same mutation induces embryonic lethality, thrombocytopenia, or identified in approximately 2% of RPS19 mutation-negative pro-
583
myelofibrosis, depending on the mouse background in which it is bands. The molecular defect of other families is the subject of
harbored. 563 numerous investigations, and novel mutations in ribosomal genes
584
On the other hand, frameshift and splice mutations encoding already implicated in the disease or in new genes (such as RPL27)
GATA1s, a protein lacking the N-terminal domain, are not only are continuously discovered.
564
associated with impaired erythropoiesis but are also found in No correlation between the nature of mutations and the different
patients with megakaryocytic leukemia in Down syndrome, 565,566 patterns of clinical expression, including age at presentation, presence
567
in newborns with transient myeloproliferative syndromes, and of malformations, and therapeutic outcome, has been documented.
568
in one adult patient with megakaryocytic leukemia. A mutation The lack of a consistent relationship between the nature of the
equivalent to that found in patients with acute megakaryoblastic mutations and the clinical phenotype implies that as yet unidentified
leukemia and Down syndrome was created in mice by N-ethyl- factors modulate the phenotypic expression of the primary genetic
585
N-nitrosourea mutagenesis screening. The reduced expression of defect in families with RPS19 mutations. Two not mutually exclu-
the full-length GATA1 was not compensated in mice by expression sive hypotheses have been proposed to explain the pathobiologic role
of GATA1s. The mutation was embryonic lethal in hemizygous of RPS19 (and RPS24) in the pathogenesis of the disease: (1) loss of
569
males and induced thrombocytopenia in heterozygous females. unknown functions not directly connected with RPS19’s structural
However, when introduced in mice the GATA1s mutation increased role in ribosomes and (2) altered protein synthesis because of poor
proliferation of a “unique” fetal stem/progenitor cell extinguished in ribosome organization. The first hypothesis was suggested by findings