Expression profiling of activated or control 5-FU bone marrow from MLL-AF4stop knockin mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE12313 | GEO | 2008/11/04
SECONDARY ACCESSION(S): PRJNA113837
REPOSITORIES: GEO
Similar Datasets
Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. To examine early, pre-leukemic changes in lymphoid cells due to Mll-AF4 expression, we infected 5-FU bone marrow cells from Mll-AF4stop knocking mice with activating (Cre-GFP) or control (MIF-GFP) retrovirus ex vivo and measured expression changes after culture under lymphoid growth conditions. Experiment Overall Design: Mll-AF4stop knock-in mice were treated with 5-FU and 5 days later their bone marrow infected ex vivo with either Cre-GFP to activate the Mll-AF4 fusion construct or with a control MIG-Cre retrovirus. GFP+ cells were sorted 2 days post-infection and cultured for 14 days under lymphoid growth conditions before total RNA was isolated for hybridization to Affymetrix expression microarrays.
2008-11-13 | E-GEOD-12313 | biostudies-arrayexpress
Project description:[original title] Gene expression analysis of leukemic samples derived from AF4-MLL- or AF4-MLL/MLL-AF4-transduced and transplanted hematopoietic stem/precursor cells in C57BL6 mice. We used microarrays to analyze the global gene expression in leukemic cells with three distinct immunophenotypes. We compared leukemic cells isolated from the bone marrow of diseased mice and compared these profiles with normal bone marrow.
2010-07-07 | E-GEOD-20519 | biostudies-arrayexpress
Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. Keywords: Cell type comparison
2008-11-04 | GSE12310 | GEO
Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. This SuperSeries is composed of the SubSeries listed below.
2008-11-04 | GSE12363 | GEO
Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. Experiment Overall Design: Total RNA from normal pro-B, pre-B, immature B and mature B lymphocytes, and from leukemic pre-B cells was isolated and hybridized to Affymetrix expresison microarrays.
2008-11-13 | E-GEOD-12310 | biostudies-arrayexpress
Project description:Malignant transformation in a multipotential precursor has recently been shown to underlie mixed phenotype acute leukaemias. In contrast, and despite the conclusive demonstration that MLL-AF4 infant ALL arises in utero. In order to address this we purified haematopoietic stem/progenitor cell (HSPC) populations from four non-lineage switching presentation infant ALL cases and one ALL presentation which went on to lineage switch at relapse. The specific MLL-AF4 fusion event was determined in unsorted samples by LDI-PCR and identified in purified populations by nested PCR. In three cases where non-lineage restricted populations were able to be purified, MLL-AF4 was identified in the CD34+CD38-CD45RA+ population (LK228, LK230, LS01), the CD34+CD38-CD45RA-CD90- multipotential progenitor population (MPP, LS01) and even a candidate CD34+CD38-CD45RA-CD90+ haematopoietic stem cell (HSC) population (LK228) Interestingly, in a single non-switched MLL-AF9 case analysed for external comparison, the fusion was only identified in CD19+ blast/B cell populations, not in any HSPC population. Unexpectedly, we were also able to identify the presence of the MLL-AF4 fusion in apparently normally differentiated CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells from the peripheral blood/bone marrow of 4/5 cases examined. This finding was further supported by single cell analysis of LS01PALL which identified the fusion in 2/22 CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells analysed. Furthermore, the matched AML sample (LS01RAML) also contained MLL-AF4 positive mature T lymphoid cells. These data imply that MLL-AF4 does not impose a complete block on normal haematopoietic differentiation, and raise the question of what additional factors contribute to leukaemic lineage determination in the setting of the MLL-AF4 translocation. To examine the functional capacity of MLL-AF4 transformed precursor cells we generated a patient-derived xenograft model using NOD-scid/IL2Rγ-/- (NSG) mice. Serial xenotransplantation identified an MLL-AF4 positive clone persisting within the human CD34+CD38-CD45RA-CD90+ compartment across four generations of mice, confirming self-renewal of this population. Together these data identify an early multipotent progenitor or HSC as the putative cell of origin for MLL-AF4 ALL. Furthermore, they demonstrate that MLL-AF4, uniquely amongst MLL fusion genes, imposes a profound lymphoid bias on the developing leukemia but without completely abolishing broader, non-malignant, haematopoietic differentiation.
2020-04-21 | GSE130142 | GEO
Project description:Malignant transformation in a multipotential precursor has recently been shown to underlie mixed phenotype acute leukaemias. In contrast, and despite the conclusive demonstration that MLL-AF4 infant ALL arises in utero. In order to address this we purified haematopoietic stem/progenitor cell (HSPC) populations from four non-lineage switching presentation infant ALL cases and one ALL presentation which went on to lineage switch at relapse. The specific MLL-AF4 fusion event was determined in unsorted samples by LDI-PCR and identified in purified populations by nested PCR. In three cases where non-lineage restricted populations were able to be purified, MLL-AF4 was identified in the CD34+CD38-CD45RA+ population (LK228, LK230, LS01), the CD34+CD38-CD45RA-CD90- multipotential progenitor population (MPP, LS01) and even a candidate CD34+CD38-CD45RA-CD90+ haematopoietic stem cell (HSC) population (LK228) Interestingly, in a single non-switched MLL-AF9 case analysed for external comparison, the fusion was only identified in CD19+ blast/B cell populations, not in any HSPC population. Unexpectedly, we were also able to identify the presence of the MLL-AF4 fusion in apparently normally differentiated CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells from the peripheral blood/bone marrow of 4/5 cases examined. This finding was further supported by single cell analysis of LS01PALL which identified the fusion in 2/22 CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells analysed. Furthermore, the matched AML sample (LS01RAML) also contained MLL-AF4 positive mature T lymphoid cells. These data imply that MLL-AF4 does not impose a complete block on normal haematopoietic differentiation, and raise the question of what additional factors contribute to leukaemic lineage determination in the setting of the MLL-AF4 translocation. To examine the functional capacity of MLL-AF4 transformed precursor cells we generated a patient-derived xenograft model using NOD-scid/IL2Rγ-/- (NSG) mice. Serial xenotransplantation identified an MLL-AF4 positive clone persisting within the human CD34+CD38-CD45RA-CD90+ compartment across four generations of mice, confirming self-renewal of this population. Together these data identify an early multipotent progenitor or HSC as the putative cell of origin for MLL-AF4 ALL. Furthermore, they demonstrate that MLL-AF4, uniquely amongst MLL fusion genes, imposes a profound lymphoid bias on the developing leukemia but without completely abolishing broader, non-malignant, haematopoietic differentiation.
2020-04-21 | GSE132396 | GEO
Project description:We developed and validated a diagnostic miniarray to recognize different subtypes of ALL. We analyzed blindly the gene expression profiling of 17 patients: 10 ALL-B, 5 ALL-T and 2 MLL/AF4. This miniarray was able to assign all samples to the correct class. We compared the transcription profiles of the leukemic samples by miniarray competitive hybridisation against an arbitrary total RNA reference prepared from normal human bone marrow. ALL-B patients: GSM50368, GSM50369, GSM50370, GSM50371, GSM50372, GSM50373, GSM50374, GSM50375, GSM50376, GSM50377 ALL-T patients: GSM50379, GSM50380, GSM50381, GSM50382, GSM50383 ALL-B patients with the specific chromosomal aberration MLL/AF4: GSM50384, GSM50385 Keywords = Acute lymphoblastic leukemia Keywords = human bone marrow Keywords = transcriptional profiling Keywords = miniarray Reference: Haematologica 2005;90:890-898 Keywords: ordered
2005-07-04 | GSE2617 | GEO
Project description:We have examined gene expression profiling of 18 children with acute lymphoblastic leukemia (ALL). In particular, the ALL patients are subdivided in three different subtypes by morphological, immunophenotypic and cytogenetical parameters: 10 ALL-B, 5 ALL-T and 3 ALL-B with the specific chromosomal aberration MLL/AF4. We compared the transcription profiles of the leukemic samples by microarray competitive hybridization against an arbitrary total RNA reference prepared from normal human bone marrow. Two replicates of each experiment were done using different microarray slides, in which the sample and reference RNAs labeled either with Cy3 or Cy5 fluorochromes were crossed in both combinations. ALL-B patients: GSM49966, GSM49967, GSM49969, GSM49970, GSM49971, GSM49972, GSM49973, GSM49974, GSM49976, GSM49977, GSM49978, GSM49979, GSM49980, GSM49981, GSM49982, GSM49983, GSM49984, GSM49985, GSM49986, GSM49987 ALL-T patients: GSM49988, GSM49989, GSM49990, GSM49991, GSM49992, GSM49993, GSM49994, GSM49995, GSM49996, GSM49997 ALL-B patients with the specific chromosomal aberration MLL/AF4: GSM49999, GSM50001, GSM50004, GSM50005, GSM50006, GSM50007 Keywords = Acute lymphoblastic leukemia (ALL) Keywords = human bone marrow Keywords = gene expression profiling Reference: Haematologica 2005;90:890-898 Keywords: ordered
2005-07-04 | GSE2604 | GEO
Project description:Infant B-acute lymphoblastic leukemias (B-ALL) that harbor MLL-AF4 rearrangements are associated with a poor prognosis. One important obstacle to progress for this patient population is the lack of models that faithfully recapitulate the short latency and aggressiveness of this disease. While current mouse models of Mll-Af4 can generate acute leukemia, not all are lymphoid, and the long latency to disease does not reflect what is seen in patients. Recent whole genome sequencing of MLL-AF4 B-ALL samples revealed a high frequency of mutations in proto-oncogenes involved in signaling pathways. Here, we demonstrate that the expression of activating mutant N-RasG12D cooperates with Mll-Af4 to generate a highly aggressive, serially transplantable B-ALL in mice. We used our novel mouse model to test the sensitivity of Mll-Af4/N-RasG12D leukemia to small molecule inhibitors, and found that dual targeting of the downstream effectors of Ras and the DNA damage response pathway through ATR inhibition induced long-term durable responses in both mouse and patient derived xenografts with both mutations in vivo. Our studies suggest that this mouse model of Mll-Af4/N-Ras B-ALL is not only a powerful tool to explore the molecular and genetic pathogenesis of this disease subtype, but also is an important preclinical discovery platform for novel therapeutics that might be used to treat patients with this disease.
2018-11-28 | GSE89560 | GEO