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

Abstract

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

A Feedback Loop Consisting of MicroRNA 23a/27a and the β-Like Globin Suppressors KLF3 and SP1 Regulates Globin Gene Expression

“…miR-15a and miR-16-1 also have been reported to elevate fetal hemoglobin expression in human trisomy 13 via MYB (20). In addition, the kit receptor/miR-221-222 complex may be involved in human hemoglobin switching (30). miR-210 has also been identified to be involved with the increased expression of the ␥-globin genes in differentiating erythroid cells (21).…”

Nitric Oxide / Cyclic Nucleotide Regulation of Globin Genes in Erythropoiesis

“…Increased miRNA-210 levels elevated Ǒ-globin levels in hereditary persistence of HbF (Bianchi et al, 2009), while the let-7 family has been associated with hemoglobin switching (Noh et al, 2009). Recently, two miRNAs, miR-221 and miR-222, have been identified to regulate HbF expression in erythropoietic cells via the kit receptor (Gabbianelli et al, 2010). miRNA-150 repression of MYB in hematopoietic progenitor cells, of human bone marrow origin, supported MYB's importance in erythroid and megakaryocytic differentiation (Lu et al, 2008).…”

Impact of epigenetic mechanisms on therapeutic approaches of hemoglobinopathies

“…Some authors indicated that Hb switching (HbF→HbA) is controlled by miRNA-221/222 complex and its overexpression caused an inhibitory effect on erythroid cell proliferation [71]. The exact molecular mechanisms controlling miRNA-221/222 expression were not well known.…”

“…The exact molecular mechanisms controlling miRNA-221/222 expression were not well known. Gabbianelli et al speculated that other mechanisms such as glucocorticoids and the transcription factor BCL11A could also contribute to the fetal-adult Hb switch [71]. Kouhkan et al.…”