Blasts in transient leukaemia in neonates with Down syndrome differentiate into basophil/mast‐cell and megakaryocyte lineages in vitro in association with down‐regulation of truncated form of GATA1

Abstract

3 SummaryMutations of GATA1, leading to aberrant expression of a truncated form of GATA1 (called GATA1s), are present in transient leukemia (TL) in neonates with Down syndrome. Using these molecular markers of TL, we investigated the growth and differentiation potential of TL blasts in the presence of hematopoietic growth factors (HGFs). Interleukin-3, stem cell factor and granulocyte-macrophage colony-stimulating factor potently stimulated the growth of TL blast progenitors and induced differentiation towards basophil/mast cell lineages, whereas thrombopoietin induced differentiation towards megakaryocytes. GATA1s was expressed in TL blasts in all 5 patients examined but was down-regulated during differentiation induced by these HGFs, while full-length GATA1 was not expressed throughout the culture. GATA1 mutations were detected in TL blasts in 4 patients, including one patient with two distinct mutations. The cells of this patient exhibited identical and only mutated sequences both before and after culture with HGFs, confirming the leukemic cell origin of these differentiated cells. Erythroid differentiation of TL blasts was not evident with any HGFs. These data indicate that TL blasts have the potential to grow and differentiate towards particular hematopoietic lineages in the presence of specific HGFs and that the down-regulation of GATA1s might be involved in blast cell differentiation.

Cytogenetic Profiles of 1213 Children with Down Syndrome in South Region of Turkey

“…DS cases are more likely to have B-cell precursor ALL, and their leukemic cells lack adverse genetic abnormalities [24]. Leukemia cells with either i(21q10) or trisomy 21 have the potential for basophil formation [25]. Worth et al [26], has reported a transient leukemic condition in a phenotypically normal newborn bearing i(21q10) clones, suggesting that the q arm of chromosome 21 contains sufficient genetic information for the development of transient leukemia.…”

Unique Myeloid Leukemias in Young Children with Down Syndrome: Cell Origin, Association with Hematopoietic Microenvironment and Leukemogenesis

“…3a), and into megakaryocytes in the presence of thrombopoietin (TPO) (Fig. 3b), by demonstrating that the differentiated cells that appeared after culture carried the same GATA1 mutations as the TL blasts did before culture (Miyauchi et al, 2010) (see section 4.2). Consistent with these in vitro data, massive increase of basophils in the peripheral blood of a patient with TL has been reported (Worth et al, 1999) and another case demonstrating pericardial effusion containing predominantly basophils has been described (Zipursky et al, 1997).…”

“…The differentiation capability of TL blasts into mature blood cells is unique for AML and might be somehow associated with the spontaneous remission of this disorder. Although TL blasts express some markers of the erythroid lineage and, in fact, erythroblasts at various stages of differentiation appeared in culture of TL blasts in the presence of erythropoietin and SCF in combination, these cells expressed full-length GATA1 but not aberrant GATA1s protein (see section 4.2) and, therefore, it was shown that these differentiated erythroid cells were derived from coexisting normal erythroid progenitors (Miyauchi et al, 2010). …”

“…The role of RUNX1 in leukemogenesis of DS-related leukemias needs to be further determined. We have recently shown that the expression level of GATA1s decreases during the process of growth factor-induced differentiation of TL blasts in vitro, indicating that GATA1s may act as a repressor of the GATA1-related proteins that induce differentiation and that the protein level of GATA1s changes depending on the cellular circumferential conditions and may be a key factor that influences the growth and differentiation of TL blasts (Miyauchi et al, 2010). Consistent with this finding, it has been described that expression of GATA1s is decreased in vivo in murine mature megakaryocytes carrying a GATA1 mutation that results in the production of GATA1s equivalent to the protein products of GATA1 mutations in DS-related leukemias (Majewski et al, 2006).…”

“…Thus, GATA1 mutations appear to occur in utero, if not in all cases, at relatively high frequency and specifically in patients with DS. Although TL and AMKL-DS are typically disorders consisting of monoclonal population of cells carrying a single type of GATA1 mutation, there have been reports of cases of TL and AMKL-DS with multiple independent clones with different GATA1 mutations in single patients (Ahmed et al, 2004;Groet et al, 2005;Miyauchi et al, 2010). In one of four AMKL-DS patients with multiple GATA1 mutations, neonatal blood spot showed 3 independent mutations but only one of these was present in AMKL-DS blasts (Ahmed et al, 2004), indicating that AMKL-DS had evolved from one of these oligoclonal cells with different GATA1 mutations that had occurred in utero.…”