CD135 (Flk2/Flt3) Expression by Human Thymocytes Delineates a Possible Role of FLT3‐Ligand in T‐Cell Precursor Proliferation and Differentiation

Bertho,; Chapel, Alain; Loilleux,; Frick,; Aigueperse,; Gorin,; Gourmelon,

doi:10.1046/j.1365-3083.2000.00746.x

Cited by 23 publications

(11 citation statements)

References 26 publications

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“…25 This may resemble aspects of FLT3 mutation in human AML. 17 In murine thymocytes, Flt3 signaling may induce myeloid differentiation, 36 consistent with changes in Hox expression. Mizuki et al 37 reported that FLT3 activation is associated with downregulation of Pu.1 and CEBPa in 32Dcl3 cells.…”

Section: Discussionmentioning

confidence: 84%

Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics

et al. 2004

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We previously reported that favorable and poor prognostic chromosomal rearrangements in acute myeloid leukemia (AML) were associated with distinct levels of HOX expression. We have now analyzed HOX expression in 50 independent adult AML patients (median age ¼ 62 years), together with FLT3 and FLT3-ligand mRNA levels, and FLT3 mutation determination. By cluster analysis, we could divide AMLs into cases with low, intermediate and high HOX expression. Cases with high expression were uniquely restricted to a subset of AMLs with intermediate cytogenetics (P ¼ 0.0174). This subset has significantly higher levels of FLT3 expression and appears to have an increase of FLT3 mutations (44%), while CEBPa mutations were infrequent (6%). FLT3 mRNA levels were correlated with the expression of multiple HOX genes, whereas FLT3 mutations were correlated with HOXB3. In some cases, FLT3 was expressed at levels equivalent to GAPDH in the absence of genomic amplification. We propose that high HOX expression may be characteristically associated with a distinct biologic subset of AML. The apparent global upregulation of HOX expression could be due to growth-factor signaling or, alternatively, these patterns may reflect a particular stage of differentiation of the leukemic cells.

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Section: Discussionmentioning

confidence: 84%

Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics

et al. 2004

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“…19 This case had strong myeloid gene expression, similar to the MLL B-ALL cases, except that high levels of granulocytic genes predominated in the FLT3-ITD T-ALL case, while monocytic genes predominated in MLL B-ALLs ( Figure S3, supplemental material). Finally, FLT3 activation has been shown to induce myeloid differentiation of T-cell precursors 47 and may contribute to the myeloid features of MLL B-ALLs as well. 12 In any case, it is unlikely that myeloid genes are related to the oncogenic transcriptional program associated with MLL (ie, up-regulation of selected major HOX genes together with MEIS1) as they are found only in MLL B-ALLs but not in MLL T-ALLs.…”

Section: Discussionmentioning

confidence: 99%

Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation

Ferrando

Armstrong

Neuberg

et al. 2003

Blood

299

228

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IntroductionTranslocations involving chromosome band 11q23 are found in a variety of hematologic malignancies, including both B-precursor and T-lineage acute lymphoblastic leukemias (B-and T-ALLs), acute myeloid leukemias (AMLs), and cases of myelodysplastic syndrome (MDS). Chromosome 11q23 rearrangements are present in most infant leukemias 1-3 and in secondary myeloid leukemias occurring after chemotherapy with topoisomerase inhibitors. [4][5][6] Invariably, such translocations generate a fusion gene encoding a chimeric protein in which the aminoterminal portion of MLL is fused to the carboxyterminal regions of more than 30 other proteins. 7,8 MLL is a mammalian homologue of the Drosophila gene trithorax, and its product functions as a master transcriptional regulator of developmental patterning and cell fate decisions. 9 The aminoterminal fragment of MLL in MLL fusion proteins uniformly includes 2 AT-hook domains and a region of homology with DNA methyltransferase, 10,11 while the carboxyterminal fragments of the numerous fusion partners show little or no structural similarity to each other.Armstrong et al 12 recently analyzed the gene expression patterns of a series of B-precursor ALLs, demonstrating a characteristic, highly distinct profile for cases with a rearranged MLL gene (MLL B-ALLs). This finding was independently confirmed in a large group of patients studied at St Jude Children's Research Hospital. 13 A major issue that remains to be addressed is the identification of the genes within the unique MLL B-ALL gene expression signature that serve as critical downstream targets during induction and maintenance of the leukemic phenotype. Among possible candidates, members of the HOX gene family are perhaps the most attractive. 8 Trithorax, the Drosophila counterpart of MLL, is required for the proper maintenance of cell type-specific patterns of HOM-C gene expression during embryogenesis. 14 In mice, heterozygous germ-line inactivation of Mll resulted in homeotic transformations of the axial skeleton associated with abnormalities in the maintenance of Hoxa7 and Hoxc9 gene expression. 9 Retroviral insertional mutagenesis experiments in mice implicated Hoxa9 in collaboration with Meis1 in myeloid leukemogenesis, 15 while subsequent transgenic studies showed that the aberrant expression of Hoxa9 and Hoxa10 in murine hematopoietic precursors induces leukemia in cooperation with Meis1. 16,17 Finally, in a very recent report, MLL was shown to regulate HOX gene expression by binding directly to promoter sequences. 18 In a previous study of human T-ALLs, 19 we identified cases with the MLL-ENL fusion oncogene, but did not compare their gene expression profiles with those of T-ALLs harboring other 19 Here we further analyze gene expression patterns in T-ALLs with MLL rearrangements and show that activation of HOXC6, HOXA9, and HOXA10, as well as the HOX gene cofactor MEIS1, defines a core gene transcriptional program shared by lymphoid leukemias expressing MLL fusion genes. Interestingly, in both the T and B line...

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“…[1][2][3] During normal lymphopoiesis, CD117/KIT is expressed by a fraction of CD34 ϩ CD3 Ϫ CD4 Ϫ CD8 Ϫ (triple-negative) thymocytes, which have not yet rearranged their T-cell receptor (TCR) genes. 4 In these thymocytes, 5 as in normal bone marrow progenitors, 6 expression of CD117/KIT coincides with that of CD135, the FLT3 receptor tyrosine kinase (RTK) that is activated by the FLT3 ligand. FLT3 and CD117/KIT share extensive structural homology.…”

Section: Introductionmentioning

confidence: 96%

“…7 Treatment with FLT3 ligand and stem cell factor elicits in vitro differentiation of CD117/KIT ϩ CD135/ FLT3 ϩ T-cell progenitors toward the myeloid lineage, whereas stem cell factor together with interleukin-7 induces development toward a mature T-cell phenotype. 5 Activating mutations of FLT3 are the most common genetic abnormality found in acute myeloid leukemia (AML) and encode a protein with constitutive RTK activity in the absence of ligand. 6 While the majority of FLT3 mutations are internal tandem duplications (ITDs) located in the juxtamembrane domain of the receptor, some leukemias instead harbor point mutations in the activation loop of the kinase domain.…”

mentioning

confidence: 99%

Activating FLT3 mutations in CD117/KIT+ T-cell acute lymphoblastic leukemias

Paietta

Ferrando

Neuberg

et al. 2004

Blood

104

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IntroductionEarly hematopoietic stem and progenitor cells express CD117/KIT, the stem cell factor receptor. 1 Detection of CD117/KIT expression by lymphoblasts in acute lymphoblastic leukemia (ALL) is rare and is restricted to T-lineage disease. 1-3 During normal lymphopoiesis, CD117/KIT is expressed by a fraction of CD34 ϩ CD3 Ϫ CD4 Ϫ CD8 Ϫ (triple-negative) thymocytes, which have not yet rearranged their T-cell receptor (TCR) genes. 4 In these thymocytes, 5 as in normal bone marrow progenitors, 6 expression of CD117/KIT coincides with that of CD135, the FLT3 receptor tyrosine kinase (RTK) that is activated by the FLT3 ligand. FLT3 and CD117/KIT share extensive structural homology. 7 Treatment with FLT3 ligand and stem cell factor elicits in vitro differentiation of CD117/KIT ϩ CD135/ FLT3 ϩ T-cell progenitors toward the myeloid lineage, whereas stem cell factor together with interleukin-7 induces development toward a mature T-cell phenotype. 5 Activating mutations of FLT3 are the most common genetic abnormality found in acute myeloid leukemia (AML) and encode a protein with constitutive RTK activity in the absence of ligand. 6 While the majority of FLT3 mutations are internal tandem duplications (ITDs) located in the juxtamembrane domain of the receptor, some leukemias instead harbor point mutations in the activation loop of the kinase domain. By contrast, FLT3 is rarely mutated in leukemic lymphoblasts, 6,[8][9][10] with the exception of the FLT3 point mutations that are found in B-lineage ALLs containing mixedlineage leukemia (MLL) gene rearrangements. 11 In this study, we asked whether the subset of early T-lineage ALL cases that express CD117/KIT also express FLT3 and harbor activating mutations of this gene. By analyzing leukemic cells from 55 adult patients with T-cell ALL (T-ALL; Eastern Cooperative Oncology Group [ECOG] trial no. E2993), we identified 3 cases with high CD117/KIT expression, and demonstrated activating FLT3 mutations in each of them-a finding with therapeutic significance in view of the availability of new inhibitors of FLT3 tyrosine kinase activity. Study design Patient samplesBone marrow or peripheral blood from 449 patients in ECOG trial no. E2993 was centrally immunophenotyped using multiparameter flow cytometry, as reported. 1,12 Consent for collection and testing of samples was obtained at study entry. B-lineage ALL was diagnosed in 380 cases; T-lineage ALL in 69 cases. Sufficient material for reverse transcriptasepolymerase chain reaction (RT-PCR) studies was available from 341 B-precursor ALLs and 55 T-lineage T-ALLs. Morphology and cytogenetics were reviewed centrally by ECOG core facilities. To investigate the association of CD117/KIT expression with T-lineage ALL, the Fisher exact test was run.All patients reported in this paper were accrued to ECOG phase 3 trial E2993. Until February 1998, patients accrued to E2993 were simultaneously entered on laboratory protocol E1485, which included written consent for immunophenotyping, cytogenetics, and selected molecular studies. Aft...

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CD135 (Flk2/Flt3) Expression by Human Thymocytes Delineates a Possible Role of FLT3‐Ligand in T‐Cell Precursor Proliferation and Differentiation

Cited by 23 publications

References 26 publications

Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics

Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics

Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation

Activating FLT3 mutations in CD117/KIT+ T-cell acute lymphoblastic leukemias

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