A signaling mechanism for growth-related expression of fetal hemoglobin

Bhanu, Natarajan V.; Trice, Tiffany A.; Lee, Y. Terry; Miller, Jeffery L.

doi:10.1182/blood-2003-05-1624

Cited by 36 publications

(41 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, recent work has provided evidence for cells of different phenotypes during ontogeny in humans 96 and, at least in vitro, the influence of certain cytokines, 101 such as stem cell factor (SCF), on the hemoglobin phenotype. Erythropoietin, a very important cell growth factor, stimulates production of erythroblasts that mature into hemoglobin producing cells and thus markedly increases the production of hemoglobin 102 but does not seem to affect directly the expression of the globin genes or their developmental control.…”

Section: Developmental Biology Of Hemoglobinmentioning

confidence: 99%

Hemoglobin research and the origins of molecular medicine

Schechter

2008

Blood

331

212

View full text Add to dashboard Cite

Much of our understanding of human physiology, and of many aspects of pathology, has its antecedents in laboratory and clinical studies of hemoglobin. Over the last century, knowledge of the genetics, functions, and diseases of the hemoglobin proteins has been refined to the molecular level by analyses of their crystallographic structures and by cloning and sequencing of their genes and surrounding DNA. In the last few decades, research has opened up new paradigms for hemoglobin related to processes such as its role in the transport of nitric oxide and the complex developmental control of the ␣-like and ␤-like globin gene clusters. It is noteworthy that this recent work has had implications for understanding and treating the prevalent diseases of hemoglobin, especially the use of hydroxyurea to elevate fetal hemoglobin in sickle cell disease. It is likely that current research will also have significant clinical implications, as well as lessons for other aspects of molecular medicine, the origin of which can be largely traced to this research tradition. (Blood. 2008;112: 3927-3938) IntroductionDuring the past 60 years, the study of human hemoglobin, probably more than any other molecule, has allowed the birth and maturation of molecular medicine. Laboratory research, using physical, chemical, physiological, and genetic methods, has greatly contributed to, but also built upon, clinical research devoted to studying patients with a large variety of hemoglobin disorders. During this period, the pioneering work of Linus Pauling, Max Perutz, Vernon Ingram, Karl Singer, Herman Lehmann, William Castle, Ruth and Reinhold Benesch, Titus Huisman, Ernst Jaffé, Ernest Beutler, and many others still active has been instrumental in these studies. Our understanding of the molecular basis of hemoglobin developmental and genetic control, structure-function relations, and its diseases and their treatment is probably unparalleled in medicine. Indeed, this field, especially during the first 25 years of the existence of the American Society of Hematology, provided the model for developments in many other areas of research in hematology and other subspecialities. This review attempts to highlight some recent developments in hemoglobin research most relevant to the hematologist in the context of the current understanding of the functions of these proteins and their genes. I am occasionally asked, "What's new in hemoglobin?" I believe that this review will show that we are still learning much that is very relevant to our understanding of human physiology and disease. Hemoglobin structureThe human hemoglobin molecules are a set of very closely related proteins formed by symmetric pairing of a dimer of polypeptide chains, the ␣-and ␤-globins, into a tetrameric structural and functional unit. The ␣ 2 ␤ 2 molecule forms the major adult hemoglobin. Their main function in mammals is to transport oxygen (O 2 ) from the lungs to tissues, but they also specifically interact with the 3 other gases, carbon dioxide (CO 2 ), carbon monoxide (CO), an...

show abstract

Section: Developmental Biology Of Hemoglobinmentioning

confidence: 99%

Hemoglobin research and the origins of molecular medicine

Schechter

2008

Blood

331

212

View full text Add to dashboard Cite

show abstract

“…In this regard, the potential role of glucocorticoids and the BCL11A HbF repressor has been mentioned above. Furthermore, in erythroid cultures of adult and cord blood HPCs, the HbF reactivation induced by KL may be mediated by Id2 and/or Tal1 transcription factors 19 (results not shown), as well as the MEK signaling pathway, 49 which in turn down-regulates the expression of the transcription factor COUP-TFII, a repressor of γ-globin genes. 50 These factors may mediate the KL stimulus on HbF synthesis, independently of or in relationship to the miR-221/222 mechanism hereby reported.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of human Hb switching: a possible role of the kit receptor/miR 221-222 complex

Gabbianelli

Testa²,

Morsilli³

et al. 2010

Haematologica

View full text Add to dashboard Cite

BackgroundThe human hemoglobin switch (HbF→HbA) takes place in the peri/post-natal period. In adult life, however, the residual HbF (<1%) may be partially reactivated by chemical inducers and/or cytokines such as the kit ligand (KL). MicroRNAs (miRs) play a pivotal role in normal hematopoiesis: downmodulation of miR-221/222 stimulates human erythropoietic proliferation through upmodulation of the kit receptor. Design and MethodsWe have explored the possible role of kit/KL in perinatal Hb switching by evaluating: i) the expression levels of both kit and kit ligand on CD34 + cells and in plasma isolated from pre-, mid-and full-term cord blood samples; ii) the reactivation of HbF synthesis in KL-treated unilineage erythroid cell cultures; iii) the functional role of miR-221/222 in HbF production. ResultsIn perinatal life, kit expression showed a gradual decline directly correlated to the decrease of HbF (from 80-90% to <30%). Moreover, in full-term cord blood erythroid cultures, kit ligand induced a marked increase of HbF (up to 80%) specifically abrogated by addition of the kit inhibitor imatinib, thus reversing the Hb switch. MiR-221/222 expression exhibited rising levels during peri/post-natal development. In functional studies, overexpression of these miRs in cord blood progenitors caused a remarkable decrease in kit expression, erythroblast proliferation and HbF content, whereas their suppression induced opposite effects. ConclusionsOur studies indicate that human perinatal Hb switching is under control of the kit receptor/miR 221-222 complex. We do not exclude, however, that other mechanisms (i.e. glucocorticoids and the HbF inhibitor BCL11A) may also contribute to the peri/post-natal Hb switch.Key words: hemoglobin switch, cord blood, cytokines, kit ligand, microRNAs.Citation: Gabbianelli M, Testa U, Morsilli O, Pelosi E, Saulle E, Petrucci E, Castelli G, Giovinazzi S, Mariani G, Fiori ME, Bonanno G, Massa A, Croce CM, Fontana L, and Peschle C. Mechanism of human Hb switching: a possible role of the kit receptor/miR 221-222 complex. Haematologica 2010;95(8):1253-1260. doi:10.3324/haematol.2009

show abstract

“…Delesyonel HPFH olan δβ 0 HPFH gibi δβ 0 talasemide de δ ve β geninde delesyon olmakla beraber δβ 0 talasemide kan tablosunda talasemik değişiklikler de mevcuttur. Homozigot olguların her ikisinde HbF %100 düzeyinde olmasına rağmen delesyonel HPFH´de kan tablosu normal, δβ 0 talasemide (29). Stres Hematopoez Sonrası HbF Yüksekliği: Akut hemoliz, akut hipoksi ve kemoterapi sonrası gelişen stres hematopoez durumunda eritroid dizi öncüllerinde farklılaşma (diferansiasyon) ve çoğalma hızlanmaktadır.…”

Section: Hbf Ve Laboratuarunclassified