Acute nonlymphocytic leukemia after transient myeloproliferative disorder in a patient with down syndrome

1990 ◽  
Vol 18 (5) ◽  
pp. 347-353 ◽  
Author(s):  
P. L. J. Barnett ◽  
A. C. L. Clark ◽  
A. C. M. Garson
Keyword(s):  
Down Syndrome ◽  
Myeloproliferative Disorder ◽  
Acute Nonlymphocytic Leukemia ◽  
Transient Myeloproliferative Disorder

scholarly journals Perturbation of fetal hematopoiesis in a mouse model of Down syndrome’s transient myeloproliferative disorder

Blood ◽  
2013 ◽  
Vol 122 (6) ◽  
pp. 988-998 ◽  
Author(s):  
Yehudit Birger ◽  
Liat Goldberg ◽  
Timothy M. Chlon ◽  
Benjamin Goldenson ◽  
Inna Muler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Myeloproliferative Disorder ◽  
Transient Myeloproliferative Disorder ◽  
Terminal Domain ◽  
Key Points ◽  
Fetal Hematopoiesis ◽  
Fetal Erythropoiesis

Key Points Transient expansion of fetal megaerythroid progenitors in ERG/Gata1s mouse is biologically similar to Down syndrome TMD. The N-terminal domain of GATA1 and the downregulation of ERG expression are essential for normal fetal erythropoiesis.

WT1 gene expression in children with Down syndrome and transient myeloproliferative disorder

2006 ◽  
Vol 30 (5) ◽  
pp. 543-546 ◽  
Author(s):  
Henrik Hasle ◽  
Bendik Lund ◽  
Charlotte Guldborg Nyvold ◽  
Peter Hokland ◽  
Mette Østergaard
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Myeloproliferative Disorder ◽  
Wt1 Gene ◽  
Children With Down Syndrome ◽  
Transient Myeloproliferative Disorder

Activating JAK3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1620-1620
Author(s):  
Tomohiko Sato ◽  
Tsutomu Toki ◽  
Rika Kanezaki ◽  
Gang Xu ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cell Lines ◽  
Sh2 Domain ◽  
Myeloproliferative Disorder ◽  
Early Event ◽  
Therapeutic Effects ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia ◽  
Transient Myeloproliferative Disorder ◽  
Transforming Activity

Abstract Children with Down syndrome (DS) have an approximately 20-fold higher incidence of leukemia than the general population. The majority of leukemia cases associated with DS are acute megakaryoblastic leukemia (AMKL). Although GATA1 mutations have been found in almost all cases of transient myeloproliferative disorder (TMD) “a preleukemia” that may be present in as many as 10% of newborn infants with DS and AMKL accompanying DS (DS-AMKL), GATA1 mutation alone may not be sufficient for development of leukemia. Following identification of acquired activating JAK3 mutations in DS-AMKL, JAK3 mutations have been reported also in TMD patients. However, the frequency and functional consequence of JAK3 mutations in TMD remain unknown. To further understand how JAK3 mutations are involved in the development and/or progression of leukemia in DS, we screened TMD patients and two DS-AMKL cell lines for JAK3 mutation, and examined the functional consequences of these JAK3 mutations. In one out of the two DS-AMKL cell lines, MGS, we identified novel JAK3 mutations (JAK3Q501H mutation in the SH2 domain and JAK3R657Q mutation in the psuedokinase domain in the same allele). JAK3Q501H and JAK3R657Q each constitutively phosphorylates STAT5 and transformes Ba/F3 cells to factor-independent growth, whereas the double mutant (JAK3Q501H and JAK3R657Q) has more potent transforming activity than each mutant. Biochemichal analysis in Ba/F3 cells revealed that the degrees of phosphorylation of STAT5 in the cells transduced with each JAK3 mutant were correlated with its transforming activity. Although we previously identified a JAK3I87T mutation in one of two TMD patients, no JAK3 mutations were detected in another 9 TMD patients. Together with the previous results, we found JAK3 mutations in each of 11 TMD and 11 DS-AMKL patients. Although the number of the patients analyzed was small, these results indicate that there are no significant differences in the frequency of JAK3 mutations between TMD and DS-AMKL. In this study, we showed for the first time that the TMD patient-derived JAK3 mutation was also an activating one. JAK3I87T transformed Ba/F3 cells to factor-independent growth. Treatment with JAK3 inhibitors (WHI-P131 and WHI-P154) resulted in a significant decrease in the growth and viability of Ba/F3 cells expressing each activating JAK3 mutant. These results suggest that the JAK3 activating mutation is an early event during the development of AMKL in DS. Furthermore these results provide a proof-of-principle that JAK3 inhibitor should have therapeutic effects on the AMKL and TMD patients carrying the activating JAK3 mutations.

A Murine Model for the Transient Myeloproliferative Disorder of Down Syndrome: Phenotypic Influence of p53 on Reversible Megakaryoblastic Disorder

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 688-688 ◽  
Author(s):  
Kamaleldin E Elagib ◽  
Lorrie L Delehanty ◽  
Adam Goldfarb
Keyword(s):  
Cell Death ◽  
Down Syndrome ◽  
Murine Model ◽  
Myeloproliferative Disorder ◽  
Collateral Damage ◽  
Platelet Counts ◽  
Transient Myeloproliferative Disorder ◽  
Amino Terminal ◽  
P53 Signaling

Abstract Infants with Down syndrome (DS) display a high incidence of a reversible megakaryoblastic proliferation known as transient myeloproliferative disorder (DS-TMD). The clinical features of DS-TMD include marrow and liver infiltration by abnormal megakaryoctic precursors. These cells show a high propensity for spontaneous death, leading to liver damage and occasionally tumor lysis syndromes. Rapid disease onset is followed by gradual spontaneous remission over weeks to months. 10–20% of patients experience disease recurrence, which manifests as irreversible acute megakaryoblastic leukemia (DS-AMKL). DS-TMD pathogenesis requires trisomy 21 combined with acquired mutations of GATA-1, a transcription factor that programs megakaryocytic and erythroid maturation. The mutant sGATA-1 consists of an 84 amino acid amino-terminal truncation with diminished transcriptional activation. Evolution of DS-TMD to DS-AMKL may involve acquisition of p53 mutations, according to a recent clinical study in which such mutations occurred in 0/7 DS-TMD and in 2/3 DS-AMKL cases. Our lab has recently developed a murine model for DS-TMD based on GATA-1 cross-talk with the P-TEFb kinase complex promoting megakaryocytic maturation (see Elagib et al., Blood, prepublication 2008). In this model, Flavopiridol inhibition of P-TEFb in GATA-1Lo mice, which have megakaryocytic deficiency of GATA-1, induces a rapid onset megakaryoblastic proliferative disorder with many features of DS-TMD: high rate of spontaneous cell death within megakaryoblasts, collateral damage to normal cells in involved tissues (marrow and spleen), defective megakaryoblastic polyploidization, aberrant coexpression of erythroid antigens on megakaryoblasts, reversibility of disease upon withdrawal of P-TEFb inhibitor, requirement for defective GATA-1 in megakaryocytes. To determine the influence of p53 signaling on disease phenotype, the GATA-1Lo mutation was bred onto a TP53−/− background, followed by in vivo P-TEFb inhibition with low-dose Flavopiridol (5 mg/kg/day for 9 days). The resultant megakaryoblastic disorder in the GATA-1Lo::TP53−/− compound mutants showed several features distinct from findings in GATA-1Lo::TP53+/+ mice. In the peripheral blood, the GATA-1Lo::TP53−/− mice showed no significant decline in platelet counts: 2/5 mice had decreases, each <20%. By contrast, the majority (11/13) of GATA-1Lo::TP53+/+ mice showed marked declines (>50%) in platelet counts with P-TEFb inhibition. On necropsy, the GATA-1Lo::TP53−/− mice showed splenomegaly of ~2-fold, while GATA-1Lo::TP53+/+ mice showed splenic shrinkage. Light microscopy revealed extensive splenic infiltration by sheets of megakaryoblasts with minimal evidence of cell death in GATA-1Lo::TP53−/− mice. Marrows from these mice also showed infiltration by megakaryoblasts, but with relative preservation of tissue architecture and bystander cellular elements. Flow cytometry on these marrows confirmed the presence of an abnornal population of megakaryocytic cells with erythroid antigen coexpression and highlighted the lack of intramedullary cell death, distinct from the extensive cell death seen in the GATA-1Lo::TP53+/+ marrows. Another histologic feature unique to the GATA-1Lo::TP53−/− mice consisted of hepatic infiltration by megakaryoblasts, without evidence of hepatocellular damage. Withdrawal of Flavopiridol for 14 days lead to clearance of megakaryoblasts from all involved organs, as seen with GATA-1Lo::TP53+/+ mice. Thus, p53 clearly modulates the phenotype of the megakaryoblastic disease seen in GATA-1Lo mice undergoing P-TEFb inhibition. In the absence of p53 signaling, this disease shows more extensive proliferation, as indicated by the splenomegaly and liver infiltration, combined with markedly decreased cell death. This decrease in cell death is accompanied by a decrease in collateral damage of bystander cells/tissues and by an ability to maintain platelet counts at pre-treatment levels. These findings provide in vivo validation that P-TEFb inhibition can activate p53 (see Gomes et al., Genes Dev., 20:601, 2006) and suggest that the cell death, tissue damage, and spontaneous regression seen in human DS-TMD could be p53-driven. Loss of p53 function may promote transformation to irreversible leukemia, but P-TEFb under such circumstances retains the potential to induce disease regression.

Transient Myeloproliferative Disorder in Neonates With and Without Down Syndrome

2008 ◽  
Vol 30 (11) ◽  
pp. 860-864 ◽  
Author(s):  
Nataly Apollonsky ◽  
Ashok Shende ◽  
Ihsane Ouansafi ◽  
Judith Brody ◽  
Mark Atlas ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Myeloproliferative Disorder ◽  
Transient Myeloproliferative Disorder

scholarly journals Transient Myeloproliferative Disorder Associated with Down Syndrome and Hypothyroidism

1995 ◽  
Vol 12 (1) ◽  
pp. 95-96
Author(s):  
Mehmet Satar ◽  
Atila Tanyeli ◽  
AytuĜ Atici ◽  
Bülent Antmen ◽  
Gülbin Bingöl
Keyword(s):  
Down Syndrome ◽  
Myeloproliferative Disorder ◽  
Transient Myeloproliferative Disorder
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