Acquired alpha-thalassemia in preleukemia is due to decreased expression of all four alpha-globin genes.

Anagnou, Nicholas P.; Ley, Timothy J.; Chesbro, Byron; Wright, Gary; Kitchens, Craig S.; Liebhaber, Stephen A.; Nienhuis, Arthur W.; Deisseroth, Albert

doi:10.1073/pnas.80.19.6051

Cited by 23 publications

(10 citation statements)

References 25 publications

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“…The ␣␤ globin mRNA ratio has been studied only in a few patients with ATMDS and was reduced to less than 0.5 in all patients analyzed. 28,31 The ␣-globin-␤-globin chain synthesis ratio is strikingly abnormal in ATMDS; 25 patients have been analyzed, and the ratio was reduced to less than 0.2 in 13 patients and was less than 0.75 in 23 cases (normal range, 0.9-1.2). In contrast, the ␣␤ globin chain synthesis ratio in MDS without thalassemia has been reported to be elevated-in some cases as high as 2.4.…”

Section: Red Blood Cell Findings and Hbh Inclusions In Patients With mentioning

confidence: 99%

Section: ␣-Thalassemia In the Context Of Hematologic Malignancymentioning

confidence: 99%

“…29,30 Patients with similar conditions were soon found to have reduced ␣-globin-␤-globin chain synthesis ratios, demonstrating unequivocally that ␣-thalassemia could occur as an acquired abnormality in patients with hematologic malignancy. 28,31 Defining the clinical and hematologic features of the acquired form of ␣-thalassemiaIn light of these reports, a registry of patients with acquired ␣-thalassemia (http://www.imm.ox.ac.uk/groups/mrc_molhaem/ home_pages/Higgs/index.html) was established in the early 1980s, and it currently includes 68 verified cases; findings for approximately half have been published. 20, Minimal criteria for inclusion in the ATMDS registry include 3 components.…”

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confidence: 99%

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Acquired α-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies

Steensma

Gibbons

Higgs

2005

Blood

105

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Abnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired ␣-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired ␣-thalassemia are now recognized: acquired deletion of the ␣-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic downregulation of ␣-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of ␣-thalassemia arising in a clonal myeloid disorder, and we discuss how ATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms. IntroductionFor more than 4 decades, the synthesis of hemoglobin during erythropoiesis has served as an excellent model for understanding mammalian gene regulation. A diverse repertoire of naturally occurring mutations of the globin genes has enabled researchers to use this system to establish many of the general principles underlying human molecular genetics and, in particular, to advance our understanding of molecular hematology. 1 Although nearly all globin mutations characterized to date have been cis-acting defects, it has recently emerged that globin synthesis may also be altered by trans-acting mutations involving erythroid-specific and general transcriptional regulators. [2][3][4] It has long been recognized that patients with hematologic malignancy and abnormal erythropoiesis may also acquire changes in hemoglobin structure or synthesis, but the molecular basis of such abnormalities remained obscure. However, recent studies of patients with myelodysplasia who acquire thalassemia have identified somatic mutations in a known trans-acting regulator of globin gene expression, ATRX (␣-thalassemia mental retardation X-linked, named after the phenotype associated with germline mutations in the gene). 5,6 Although these new observations will undoubtedly increase our understanding of how globin gene expression is normally controlled, they may also point to common genetic or epigenetic mutations that contribute to the development or progression of myelodysplasia. Normal structure and expression of globin gene clustersThe synthesis of hemoglobin is controlled by 2 developmentally regulated multigene clusters: the ␣-like globin cluster on chromosome 16 (5Ј--␣2-␣1-3Ј) and the ␤-like globin cluster on chromosome 11 (5Ј-⑀-G␥-A␥-␦-␤-3Ј) ( Figure 1). Coordinated expres...

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Section: Red Blood Cell Findings and Hbh Inclusions In Patients With mentioning

confidence: 99%

Section: ␣-Thalassemia In the Context Of Hematologic Malignancymentioning

confidence: 99%

mentioning

confidence: 99%

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Acquired α-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies

Steensma

Gibbons

Higgs

2005

Blood

105

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“…The excess of 13-globin chains in the erythrocytes of these patients is due to the loss of expression of at least three of the four a-globin genes normally present in diploid erythroid cells (1). Previous studies in our laboratory (2), as well as those of Weatherall and coworkers (3,4), have suggested that hemoglobin H disease can also be acquired during the evolution of preleukemia or myeloproliferative disease. In these latter patients, the transcriptional activity of all four of the a-globin genes appears to be reduced to 10% of normal.…”

mentioning

confidence: 88%

S1 nuclease analysis of alpha-globin gene expression in preleukemic patients with acquired hemoglobin H disease after transfer to mouse erythroleukemia cells.

Helder¹,

Deisseroth²

1987

Proc. Natl. Acad. Sci. U.S.A.

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The loss of alpha-globin gene transcriptional activity rarely occurs as an acquired abnormality during the evolution of myeloproliferative disease or preleukemia. To test whether the mutation responsible for the loss of alpha-globin gene expression (hemoglobin H disease) in these patients is linked with the alpha-globin genes on chromosome 16, we transferred chromosome 16 from preleukemic patients with acquired hemoglobin H disease to mouse erythroleukemia cells and measured the transcriptional activity of the human alpha-globin genes. After transfer to mouse erythroleukemia cells, the expression of human alpha-globin genes from the peripheral blood or marrow cells of preleukemic patients with acquired hemoglobin H disease was similar to that of human alpha-globin genes transferred to mouse erythroleukemia cells from normal donors. These data showed that factor(s) in the mouse erythroleukemia cell can genetically complement the alpha-globin gene defect in these preleukemia patients with acquired hemoglobin H disease and suggest that altered expression of a gene in trans to the alpha-globin gene may be responsible for the acquisition of hemoglobin H disease in these patients.

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“…65,66 PKCa stabilizes neuronal transcripts by inducing redistribution of Hu proteins from the nucleus to the cytoskeleton. 67 Although AMP-activated protein kinase (AMPK) has also been shown to cause nuclear export of HuR, 68 direct phosphorylation of HuR has not been shown. Nonetheless, HuR phosphorylation may be necessary for its function -binding of cytoplasmic HuR to p21 transcript has been shown to be Erk-dependent.…”

Section: Stabilizing Proteinsmentioning

confidence: 99%

mRNA stability control: a clandestine force in normal and malignant hematopoiesis

Steinman

2007

Leukemia

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This review addresses the scope of influence of mRNA decay on cellular functions and its potential role in normal and malignant hematopoiesis. Evidence is emerging that leukemic oncogenes and hematopoietic cytokines interact with mRNA decay pathways. These pathways can co-regulate functionally related genes through specific motifs in the 3 0 -untranslated region of targeted transcripts. The steps that link external stimuli to transcript turnover are not fully understood, but include subcellular relocalization or post-transcriptional modification of specific transcript-stabilizing or -destabilizing proteins. Improper functioning of these regulators of mRNA turnover can impede normal cellular differentiation or promote cancers. By delineating how subsets of transcripts decay in synchrony during normal hematopoiesis, it may be possible to determine whether this post-transcriptional regulatory pathway is hijacked in leukemogenesis.

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Acquired alpha-thalassemia in preleukemia is due to decreased expression of all four alpha-globin genes.

Cited by 23 publications

References 25 publications

Acquired α-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies

Acquired α-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies

S1 nuclease analysis of alpha-globin gene expression in preleukemic patients with acquired hemoglobin H disease after transfer to mouse erythroleukemia cells.

mRNA stability control: a clandestine force in normal and malignant hematopoiesis

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