Niche Requirements of Transient Leukemia Cells in Down Syndrome

Abstract Abstract 1753 Background. Young children with Down syndrome (DS; constitutional trisomy 21) have a 150-fold higher risk of developing acute myeloid leukemia (AML). Blast cells are detectable in the peripheral blood of approximately 10% of newborns with DS; these indicate the frequent presence of a preleukemic disorder termed transient leukemia (TL)/transient myeloproliferative disorder (TMD). This disorder of fetal hematopoiesis is triggered by somatic mutations of the hematopoietic transcription factor GATA1 exclusively in the context of cellular trisomy 21. The majority of TL cases undergo spontaneous resolution by unknown mechanisms. In contrast, approximately 1 of 5 cases progress to AML within a defined postnatal window (first 4 years of life). We hypothesized that the resolution of TL results from the absence of essential environmental cues following the developmental transition from prenatal fetal liver (FL) hematopoiesis to postnatal blood cell formation in the bone marrow (BM). We previously observed that primary blasts of human TL lack the proliferative expansion in the bone marrow environment of xenotransplant recipients that is observed for blasts of DS-AML. Consequently, we aimed to identify the signals provided by the FL niche that support the survival and proliferation of human TL cells. Methods and Results. To determine the differential impact of the hematopoietic niche provided by FL and postnatal BM on TL cells, we cultured primary human TL cells on murine stromal cell lines that were derived either from FL (AFT024) or adult BM (MS-5). The absolute number of primary TL cells increased >80-fold during culture on FL-derived stromal cells for 2 weeks. In contrast, BM-derived MS-5 stromal cells supported only a moderate expansion (<10-fold), which was associated with enhanced induction of apoptotic cell death and evidence of partial myeloid differentiation. Direct interaction between TL and stromal cells – acting co-operatively with soluble growth factors – appears indispensable for the maintenance of TL cell survival and stimulation of proliferation. Functional studies identified the very late antigen-4 [VLA-4 (CD49d)]/vascular cell adhesion molecule-1 (VCAM-1) binding partners as putative mediator of this interaction. Furthermore, insulin-like growth factor 2 (IGF-2) supplementation augmented the proliferation of TL cells specifically in the context of the FL niche. Neither IGF-2 alone or in combination with BM-derived stroma promoted expansion of TL cells. Work currently underway aims at identification of additional molecular pathways involved in TL-cell regulation, including elucidating the potential role of Notch signaling in development and maintenance of TL cells. Conclusions. Cooperative signals that are preferentially provided by the hematopoietic environment of the fetal liver support the survival and proliferation of human TL cells. These signals consist of a combination of cell-cell contact, in part mediated by VLA-4/ VCAM1, and soluble growth factors such as IGF-2. The identification and disruption of signaling pathways that are essential for the survival and expansion of TL blasts has the potential to prevent development of AML in children with Down syndrome by targeted elimination of the preleukemic TL clone. Disclosures: No relevant conflicts of interest to declare.

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Stroma cells and Monocytes make Multiple Myeloma Cells Active In Bone Marrow Microenviroment

Blood ◽

10.1182/blood.v122.21.5333.5333 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5333-5333

Author(s):

Hiroshi Ikeda ◽

Tadao Ishida ◽

Toshiaki Hayashi ◽

Yuka Aoki ◽

Yasuhisa Shinomura

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Bone Marrow ◽

Cell Lines ◽

Stromal Cells ◽

Conflicts Of Interest ◽

Cell Contact ◽

Drug Induced ◽

Myeloma Cells

Abstract The Bone marrow (BM) microenvironment plays crucial role in pathogenesis of multiple myeloma　(MM). Paracrine secretion of cytokines in BM stromal cells promotes multiple myeloma cell proliferation and protects against drug-induced cytotoxicity. In current study, monocytes, component of BM cells, can directly promote mesenchymal stem cells osteogenic differentiation through cell contact interactions. Down-regulation of inhibitors such as DKK1 drives the differentiation of mesechymal stem cells into osteoblasts. In this study, we examined the role of monocytes as a potential niche component that supports myeloma cells. We investigated the proliferation of MM cell lines cultured alone or co-cultured with BM stromal cells, monocytes, or a combination of BM stromal cells and monocytes. Consistently, we observed increased proliferation of MM cell lines in the presence of either BM stromal cells or monocytes compared to cell line-only control. Furthermore, the co-culture of BM stromal cells plus monocytes induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, BMSCs and monocytes decreased the rate of apoptosis of myeloma cells. Our results therefore suggest that highlights the role of monocyte as an important component of the BM microenvironment. Disclosures: No relevant conflicts of interest to declare.

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Understanding Pre-Leukemia in Trisomy 21 Human HSC and Modeling Progression Towards Down Syndrome Associated Leukemia Using CRISPR/Cas9 at Single Cell Resolution

Blood ◽

10.1182/blood-2019-129259 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2531-2531 ◽

Cited By ~ 1

Author(s):

Elvin Wagenblast ◽

Olga I. Gan ◽

Maria Azkanaz ◽

Sabrina A. Smith ◽

Joana Araújo ◽

...

Keyword(s):

Down Syndrome ◽

Single Cell ◽

Trisomy 21 ◽

Childhood Leukemia ◽

Fetal Liver ◽

Cohesin Complex ◽

Erythroid Cells ◽

Transient Leukemia

Leukemia is the most common cancer in children. Sequencing data from identical twins suggests that the first genetic alterations in childhood leukemia occur in utero. Children with Down syndrome (Trisomy 21, T21) have an increased risk of childhood leukemia. In 30% of newborns with Down syndrome, a transient pre-leukemia disease occurs, which is characterized by a clonal proliferation of immature megakaryocytes carrying somatic mutations in the GATA1 transcription factor. These acquired GATA1 mutations lead to the expression of an N-terminal truncated protein (GATA1-Short). In 20% of the cases, acute megakaryoblastic leukemia (AMKL) evolves from the pre-leukemia by acquisition of additional genetic mutations in the transient leukemia clone, predominantly in genes of the cohesin complex. It is hypothesized that this represents a multi-step process of leukemogenesis with three distinct genetic events: T21, GATA1-Short and additional cohesin mutations. Yet, it remains unclear how an extra copy of chromosome 21 predisposes towards leukemia, the mechanisms of leukemic transformation and the interplay between each genetic component. Therefore, we wanted to establish a tractable human model system to investigate the initiation and evolution of transient leukemia and AMKL using CRISPR/Cas9 genome editing in primary human hematopoietic stem cells (HSCs). To model the initiation of Down syndrome associated pre-leukemia, we utilized both neonatal cord blood and fetal liver derived LT-HSCs and other progenitor populations to express either the short or long isoform of GATA1 (GATA1-Short or GATA1-Long). This was carried out using an improved methodology that permits the in vitro and in vivo functional interrogation of CRISPR/Cas9 edited human LT-HSCs at the single cell level (Wagenblast et al., bioRxiv 609040). Importantly, in this case, expression of either GATA1 isoform remained under the regulatory control of the endogenous promoter. Culture of single LT-HSC, short-term (ST-HSC) and myelo-erythroid progenitors (MEP) revealed a drastic shift towards megakaryocytic lineage output upon exclusive expression of GATA1-Short compared to control or GATA1-Long, regardless of the developmental source of the derived cells. To investigate the functional consequences of exclusive GATA1-Short expression in LT-HSCs in vivo, we performed near-clonal xenotransplantation assays in NSG and NSGW41 mice. Strikingly, GATA1-Short edited LT-HSCs injected mice displayed a higher percentage of human CD41+CD45- megakaryocytic lineage derived cells and a decrease in human GlyA+CD45- erythroid cells compared to control. Morphological analysis revealed more immature forms of erythroid cells and fewer enucleated erythrocytes in GATA1-Short edited LT-HSCs injected mice. In order to add an additional genetic determinant to our model, we utilized T21 fetal liver derived LT-HSCs. Un-manipulated T21 LT-HSCs and other progenitor populations showed a bias towards erythroid, myeloid and megakaryocytic lineages at the expense of lymphoid fates. In vitro, the combination of T21 and CRISPR/Cas9-mediated GATA1-Short in LT-HSCs led to an increase in megakaryocytic lineage output, while decreasing erythroid output. This phenotype was similar to what was observed in normal karyotype fetal liver derived LT-HSCs. However, near clonal transplantation of GATA1-Short edited T21 LT-HSCs in NSG mice generated exclusive CD33+ myeloid grafts with disproportionate high levels of CD41+CD45- megakaryocytic lineage derived cells compared to T21 control. In addition a distinct CD34+CD41+CD71+CD45+ population was present. Thus, this phenotype is reminiscent of Down Syndrome associated transient leukemia. In summary, by using an improved CRISPR/Cas9 single cell methodology we show how GATA1 regulates lineage fate in normal and T21 LT-HSCs and other progenitor populations. Importantly, we show for the first time a humanized mouse model of Down syndrome associated transient leukemia, which was induced from T21 human fetal liver derived LT-HSCs engineered to express GATA1-Short. Current studies focus on adding additional mutations of the cohesin complex to progress transient leukemia to AMKL. Disclosures No relevant conflicts of interest to declare.

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Trisomy 21 Expands the Megakaryocyte-Erythroid Progenitor Compartment in Human Fetal Liver-Implications for Down Syndrome AMKL.

Blood ◽

10.1182/blood.v108.11.563.563 ◽

2006 ◽

Vol 108 (11) ◽

pp. 563-563 ◽

Cited By ~ 3

Author(s):

Oliver Tunstall-Pedoe ◽

Josu de la Fuente ◽

Phillip R. Bennett ◽

Nicholas M. Fisk ◽

Paresh Vyas ◽

...

Keyword(s):

Bone Marrow ◽

Down Syndrome ◽

Trisomy 21 ◽

Fetal Liver ◽

Fetal Blood ◽

Fetal Bone ◽

Cd34 Cells ◽

Progenitor Compartment ◽

Gata1 Mutation

Abstract Children with Down syndrome (DS) have a uniquely high frequency of acute megakaryoblastic leukemia (AMKL)- ~500-fold increased compared to children without trisomy 21 (T21). At least two genetic events are required but are not sufficient for DS-AMKL: T21 and N-terminal truncating mutations in the key megakaryocytic transcription factor GATA1. This tight association of T21 with GATA1 mutations and the development of AMKL in a narrow temporal window (fetal life-5yrs) makes DS-AMKL a highly informative model of multi-hit leukemogenesis in which the first steps occur in utero. However, the individual contributions of T21 and mutant GATA1 in the leukemogenesis are unclear. To specifically investigate the role of T21 in DS-AMKL and why leukemia-initiation is confined to fetal (or early post-natal) life we have studied fetal hemopoiesis in DS during the second and third trimester in 16 fetuses (gestational age 15–37 weeks) where an antenatal diagnosis of DS with T21 was made by amniotic fluid fetal cell karyotyping. Samples of fetal blood (n=13), fetal liver (n=9) and fetal bone marrow (n=8) were screened for mutations in the GATA1 gene genomic DNA by DHPLC or direct sequencing (sensitivity of detecting a GATA1 mutation is 1–5% by DHPLC). No GATA1 mutations were detected. This allowed us to study the impact of T21 independent of GATA1 mutation on fetal hemopoiesis. DS fetuses showed marked qualitative and quantitative abnormalities in hemopoiesis. While the total number of CD34+ cells in DS and normal fetal liver were comparable, DS fetuses had a striking increase in bi-potential megakaryocyte-erythroid progenitors (MEP; CD34+CD38+FcgloCD45RA+− 74.4% vs 27.0% of fetal liver CD34+/CD38+ cells. Peripheral blood from all DS fetuses studied compared to normal fetal blood samples showed dysmegakaryopoiesis (abnormally shaped and/or giant platelets and MK fragments), dyserythropoiesis (macrocytes, poikilocytes, basophilic stippling), increased numbers of blast cells and also had an increased percentage of MEPs − 40.3% vs 26.9%. By contrast, there was no difference in the number of MEP nor erythroid or MK lineage morphology in DS fetal bone marrow compared to normal fetal bone marrow. CD34+ cells from DS fetal liver and fetal blood expressed both fl GATA1 and GATA1s mRNA indicating that dysmegakaryopoiesis and erythropoiesis were not due to lack of expression of fl GATA1. These data indicate, for the first time, that T21 by itself profoundly disturbs megakaryopoiesis and erythropoiesis and leads to an increased of frequency of MEP. This has important implications since it provides a testable hypothesis for the role of T21 in the initiating step of AMKL, namely that T21 expands a fetal liver-derived progenitor compartment which forms a substrate upon which GATA1 mutations then confer a further selective advantage.

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Interleukin-3 and interleukin-7 are alternative growth factors for the same B-cell precursors in the mouse

Blood ◽

10.1182/blood.v85.8.2045.bloodjournal8582045 ◽

1995 ◽

Vol 85 (8) ◽

pp. 2045-2051 ◽

Cited By ~ 39

Author(s):

TH Winkler ◽

F Melchers ◽

AG Rolink

Keyword(s):

Bone Marrow ◽

Growth Factors ◽

B Cells ◽

B Cell ◽

Light Chain ◽

Stromal Cells ◽

Fetal Liver ◽

Surrogate Light Chain ◽

Interleukin 7 ◽

Precursor B Cells

Clones and lines of precursor (pre) B cells can be established by limiting dilutions of unseparated cell suspensions of fetal liver or bone marrow on stromal cells in the presence of interleukin (IL)-7. When IL-3 is used instead of IL-7, cultures are regularly overgrown by different precursor cells of the myeloid lineage, as well as by adherent cells that inhibit pre-B-cell expansion. However, in the presence of either IL-7 or IL-3, clones of pre-B cells can be established on stroma cells at frequencies near one in one when the cultures are initiated with cell sorter purified CD45RO (B220)+/c-kit+ fetal liver or bone marrow derived pre-B cells. Clones grown on stromal cells in the presence of IL-7 can be regrown in IL-3, and vice versa. Pre-B cells that proliferate on stromal cells in the presence of IL-7 or IL-3 have the same phenotype, ie, are B220+ c-kit+, CD43+, and surrogate light chain+. Removal of the growth factors (IL-7, respectively IL-3) from the cultures results in differentiation to surface immunoglobulin (slg) positive, c-kit-, CD43-, surrogate light chain-B cells, a fraction of which is lipopolysaccharide (LPS) responsive as shown by IgM secretion. These results show that IL-7 and IL-3 stimulate largely overlapping populations of precursor B cells from bone marrow to proliferate for long periods of time in the presence of stromal cells. Thus, IL-7 and IL-3 are alternative growth factors for the same pre-BI cell.

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Increased Interferon-αa Signaling During Megakaryocyte Ontogeny: Implications for the Spontaneous Resolution of Down Syndrome Transient Myeloproliferative Disorder.

Blood ◽

10.1182/blood.v114.22.1272.1272 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1272-1272 ◽

Cited By ~ 1

Author(s):

Karen Wieland ◽

Andrew Woo ◽

Thomas Akie ◽

Alan B. Cantor

Keyword(s):

Bone Marrow ◽

Down Syndrome ◽

Conflicts Of Interest ◽

Fetal Liver ◽

Myeloproliferative Disorder ◽

Spontaneous Resolution ◽

Chromosome 21 ◽

Dependent Manner ◽

Wild Type ◽

Transient Myeloproliferative Disorder

Abstract Abstract 1272 Poster Board I-294 About ten percent of infants with Down syndrome (DS) are born with a transient myeloproliferative disorder (DS-TMD), which spontaneously resolves within the first few months of life. However, the basis for this resolution remains unknown. Acquired mutations leading to exclusive production of a short isoform of the transcription factor GATA-1 (GATA-1s) occur in all cases of DS-TMD, and knock-in mice that exclusively produce GATA-1s have hyperproliferation of megakaryocytes during early fetal liver hematopoiesis, but not during later developmental stages. In this study, we found striking upregulation of the interferon-αa (IFN-αa) receptor and multiple IFN-αa responsive genes, including Ifi203, Ifi205, Irf-1, Irf-8, and Ifitm6, in immunophenotypically isolated megakaryocyte progenitor cells (MkPs) from bone marrow versus embryonic day 13.5 (e13.5) fetal liver of wild type mice. These differences were confirmed at the protein level in megakaryocytes by in situ immunohistochemistry. Addition of IFN-αa to GATA-1s containing e13.5 fetal liver MkPs reduces their hyperproliferation in vitro in a dose-dependent manner. Conversely, injection of neutralizing IFN-αa/β antibodies, but not control IgG, into adult GATA-1s mice markedly increases the percentage of bone marrow CD41+ cells and morphologically recognizable megakaryocytes, in contrast to wild type mice. We propose that increases in IFN-αa signaling during megakaryocyte ontogeny may account for the developmental stage-specific effects of GATA-1s on megakaryocyte hyperproliferation, and possibly the spontaneous resolution of DS-TMD. Interestingly, the genes encoding the IFN-αa/β receptor are located on human chromosome 21 and are expressed at 1.6 times that in trisomy versus disomy 21 cells. We speculate that increased interferon alpha signaling during embryogenesis may be the basis for the strong selective pressure for GATA-1s producing mutations in trisomy 21 fetuses in the first place. Disclosures No relevant conflicts of interest to declare.

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Chromosome 21 Encoded RUNX1 and ETS-2 Overexpression in Regenerating Hematopoiesis in Children with Down Syndrome - Implications for Leukemiogenesis?.

Blood ◽

10.1182/blood.v106.11.4373.4373 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4373-4373

Author(s):

Dirk Reinhardt ◽

Kristin Wortmann ◽

Miriam Kolar ◽

Jan H. Klusmann ◽

Ulrike Puhlmann ◽

...

Keyword(s):

Bone Marrow ◽

Down Syndrome ◽

Trisomy 21 ◽

Bone Marrow Cells ◽

Gene Dosage ◽

Gene Array ◽

Chromosome 21 ◽

Children With Down Syndrome ◽

Increased Risk ◽

Hematological Disorder

Abstract Children with Down Syndrome (DS) are at an 150 fold increased risk to develop acute megakaryoblastic leukemia (AMKL) within the first 4 years of life. About 10% of newborns with trisomy 21 showed transient myeloproliferative disorder (TMD). Although mutations of the transcriptional factor GATA1, resulting in the shortened GATA1s have been shown in almost all blasts in DS-AMKL and TMD the predisposition to leukemiogenesis related to trisomy 21 is not clear. TMD occurred during embryonic stress hematopoiesis leading to the hepatic proliferation of the GATA1s positive blasts. Typically blasts disappeared within the first 3 month of live, however after a median time of 1.3years (0.6 to 3.7 years) 20% of the children suffered AMKL and required intensive cytostatic treatment. The expression of chromosome 21 encoded hematological transcription factors (TFs) such RUNX1, ETS-2 and ERG were analysed in leukemic blasts from DS- TMD(n=7), DS-AMKL (n=25), DS without hematological disorder (n=10), AMKL (n=10) and healthy controls (n=7) by qRT-PCR. Results: No increase of RUNX1, ETS-2 and ERG expression could be shown. By contrast, ERG was decrease in all leukemias and in DS without hematological disorder (p Anova.<0.002). GATA1s was significantly overexpressed in TMD and DS-AMKL (pAnova <0.02), whereas GATA1 expression in AMKL and controls was not changed. GATA2 was elevated (pAnova <0.01) in all megakaryoblastic leukemias, with or without DS (pAnova <0.0001). PU.1, typically associated with early lymphatic differentiation and granulopoiesis was down regulated in all megakaryoblastic leukemias and, surprisingly, in DS without hematological disorder. This confirmed previously reported results by gene-array analysis1. To get further insight in the predisposition caused by trisomy 21 we analysed regenerating hematopoiesis in DS (n=14) partly resembling embryonic stress hematopoiesis. Correlated to the amount of bone marrow activation (CD38 positivity) a myeloid cell population (CD13/CD33 positive); with the co-expression of CD56 (NCAM) and CD36 (thrombospondin-receptor) could be detected by immunophenotyping (median percentage all nucleated bone marrow cells: 73±10%). In children without DS but regenerating hematopoiesis (n=41) a similar population of 4.6±1.8% (p<0.00001) could be detected. For further analysis the CD33/CD56 positive cells were sorted (FACSVantage). The cells showed normal myeloid morphology and differentiation, lack of GATA1s mutation, but an aberrant TF expression pattern. RUNX1 was 10-fold and ETS-2 5-fold higher expressed compared to controls (p<0.012). Summarized, (1) DS-AMKL and TMD leukemic blasts showed no general gene-dosage effect. However, (2) in stimulated bone marrow (stress hematopoiesis) trisomy 21 led to an overexpression of chromosome 21 encoded TFs, which might contribute to leukemiogenesis.

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Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3+ T reg induction capacity

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02176-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yi Yu ◽

Alejandra Vargas Valderrama ◽

Zhongchao Han ◽

Georges Uzan ◽

Sina Naserian ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Immune Responses ◽

Molecular Mechanisms ◽

Fetal Liver ◽

Cytotoxic T Cells ◽

Cell Contact ◽

Adult Bone Marrow ◽

Adult Bone

Abstract Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

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Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽

10.38192/1.6.1.c9 ◽

2019 ◽

Vol 6 (1) ◽

pp. c9

Author(s):

Triya Chakravorty ◽

Irene Roberts

Keyword(s):

Down Syndrome ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Trisomy 21 ◽

Children With Down Syndrome ◽

Transient Abnormal Myelopoiesis ◽

Increased Risk ◽

Leukaemic Cells ◽

Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

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