Immunophenotype of Down Syndrome Acute Myeloid Leukemia and Transient Myeloproliferative Disease Differs Significantly from Other Diseases with Morphologically Identical or Similar Blasts

Langebrake, Claudia; Creutzig, U.; Reinhardt, Dirk

doi:10.1055/s-2005-836510

Cited by 88 publications

(88 citation statements)

References 16 publications

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“…In this study, we have labeled most DS leukemia cases as AMKL, keeping the differences in the expression of megakaryocytic and erythroid markers between DS-and non-DS-AMKL in mind, as described recently in ref. 13. We sequenced exon 2 of GATA1 from similar numbers of TMD-AMKL͞DS-AMKL and non-DS-AMKL samples (Table 4).…”

Section: Methodsmentioning

confidence: 99%

Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

Bourquin

Subramanian

Langebrake

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

170

198

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Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX͞TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used crossspecies comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.Down syndrome ͉ GATA1

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Section: Methodsmentioning

confidence: 99%

Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

Bourquin

Subramanian

Langebrake

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

170

198

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“…An expression of either CD41, CD42 or CD61 is required for the diagnosis of AML-M7 (9,10). CD41 has also been described as a marker for TMD (7,13,29). Technical problems, including adherence of platelets to leukocytes including monocytes and blast cells can lead to false positive results for these markers (15).…”

Section: Discussionmentioning

confidence: 99%

“…Karandikar et al examined the immunophenotype of 18 patients with TMD and DS-AML and found inconclusive results for the expression of CD41 or CD61 in 4/18 cases (22%) due to background staining of neutrophil leukocytes and monocytes (16). Langebrake et al described expression of CD41 or CD61 in only 57% of TMD and 65% of DS-AML patients, Klusmann et al in 62% of TMD patients (13,25). These technical imprecisions and the lack of sensitivity for known TMD and M7 markers underlie the need for new markers in the diagnosis of these entities.…”

Section: Discussionmentioning

confidence: 99%

“…According to the European Group for the Immunological Characterization of Leukemias (EGIL) classification, CD41 and CD61 are considered as markers of the megakaryocytic lineage (11). CD41 is expressed throughout all stages of maturation of platelets and has therefore been described as a specific marker for AML-M7 and TMD (12)(13)(14). However, adherence of platelets to leukocytes including monocytes and blast cells can lead to false positive results for this marker (15,16).…”

mentioning

confidence: 99%

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Blast cell deficiency of CD11a as a marker of acute megakaryoblastic leukemia and transient myeloproliferative disease in children with and without Down syndrome

Boztug

Schumich

Pötschger

et al. 2013

Cytometry Part B Clinical

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“…8 Recent reports showed that KIT is also expressed in almost all TL patients. 5,9 However, little is known about the expression level of KIT and the functional roles of SCF/KIT pathway in TL.…”

Section: Introductionmentioning

confidence: 99%

The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

et al. 2008

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Transient leukemia (TL) has been observed in approximately 10% of newborn infants with Down syndrome (DS). Although treatment with cytarabine is effective in high-risk TL cases, approximately 20% of severe patients still suffer early death. In this study, we demonstrate abundant KIT expression in all 13 patients with GATA1 mutations, although no significant difference in expression levels was observed between TL and acute myeloid leukemia. Stem cell factor (SCF) stimulated the proliferation of the TL cells from five patients and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation effectively in vitro. To investigate the signal cascade, we established the first SCF-dependent, DS-related acute megakaryoblastic leukemia cell line, KPAM1. Withdrawal of SCF or treatment with imatinib induced apoptosis of KPAM1 cells. SCF activated the RAS/MAPK and PI3K/AKT pathways, followed by downregulation of the pro-apoptotic factor BIM and upregulation of the anti-apoptotic factor MCL1. Although we found novel missense mutations of KIT in 2 of 14 TL patients, neither mutation led to KIT activation and neither reduced the cytotoxic effects of imatinib. These results suggest the essential role of SCF/KIT signaling in the proliferation of DSrelated leukemia and the possibility of therapeutic benefits of imatinib for TL patients.

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Immunophenotype of Down Syndrome Acute Myeloid Leukemia and Transient Myeloproliferative Disease Differs Significantly from Other Diseases with Morphologically Identical or Similar Blasts

Cited by 88 publications

References 16 publications

Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

Blast cell deficiency of CD11a as a marker of acute megakaryoblastic leukemia and transient myeloproliferative disease in children with and without Down syndrome

The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

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