Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome.

  title={Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome.},
  author={Claudia S. Huettner and Steffen Koschmieder and Hiromi Iwasaki and Junko Iwasaki-Arai and Hanna S. Radomska and Koichi Akashi and Daniel Geoffrey Tenen},
  volume={102 9},
The BCR/ABL fusion protein is found in more than 90% of patients with chronic myeloid leukemia (CML) as well as in a subset of patients with acute B-cell leukemia. We have previously described a transgenic model for an inducible and reversible acute B-cell leukemia caused by p210 BCR/ABL. Here, we describe a new model of an inducible BCR/ABL disease by directing the expression of the oncogene to megakaryocytic progenitor cells within the murine bone marrow using the tetracycline-responsive… 

Figures and Tables from this paper

Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis.

This mouse model recapitulates many characteristics of human chronic myeloid leukemia (CML) and may help elucidate basic leukemogenic mechanisms in CML stem cells during disease initiation and progression.

Role of SPA-1 in phenotypes of chronic myelogenous leukemia induced by BCR-ABL-expressing hematopoietic progenitors in a mouse model.

It is suggested that endogenous SPA-1 plays a significant role in regulating expansion and/or survival of BCR-ABL(+) leukemic progenitors albeit partial repression by BCR -ABL and that Rap1 signal may represent a new molecular target for controlling leukeic progenitor cells in CML.

Functional Modeling of Genes Upregulated in Chronic Myeloid Leukemia

The results suggest that IL1RAP is a promising target for novel therapeutic approaches in CML and SOCS2 is dispensible for normal hematopoiesis and CML pathogenesis.

Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

A humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis.

C/EBPβ promotes BCR–ABL-mediated myeloid expansion and leukemic stem cell exhaustion

Results suggest that C/EBPβ is involved in BCR–ABL-mediated myeloid expansion and further elucidation of the molecular mechanisms underlying the C/ EBPβ-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.

Transgenic expression of human cytokines in immunodeficient mice does not facilitate myeloid expansion of BCR-ABL1 transduced human cord blood cells

A massive expansion of human T-cells and macrophages/histiocytes was observed and it was suggested that while BCR-ABL1 contributes to the inflammatory reaction, the presence of normal human hematopoietic cells is detrimental for NSGS mice.

Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice

It is demonstrated that overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induces acute leukemia in a transgenic model for CML.

Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia.

It is demonstrated that enhanced expression of p210BCR/ABL and deregulated expression of Zfp423/ZNF423 contribute to CML BC.



Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias.

The results demonstrate that the expression of p210bcr/abl in hematopoietic progenitor cells in transgenic mice can contribute to two clinically distinct hematoplastic malignancies, CML and ALL, indicating that this transgenic system provides a novel transgenic model for human Ph1-positive leukemias.

Modulation of p210(BCR-ABL) activity in transduced primary human hematopoietic cells controls lineage programming.

It is shown that primitive human CD34(+) cord blood cells, including multipotent as well as granulopoietic- and erythroid-restricted progenitors, can be efficiently transduced with a MSCV-BCR-ABL-IRES-GFP retrovirus, resulting in the sustained expression by their progeny of very high levels of tyrosine phosphorylated p210(BCR)-ABL.

Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome.

It is demonstrated that P210bcr/abl expression can induce chronic myelogenous leukemia and retrovirus-mediated expression of the protein provides a murine model system for further analysis of the disease.

A bcr-v-abl oncogene induces lymphomas in transgenic mice

It is demonstrated that bcr-v-abl is tumorigenic in vivo and provide a new animal model for lymphomagenesis and demonstrates that transcription is activated by a low-frequency somatic event.

Expression of p210bcr/abl by metallothionein promoter induced T-cell leukemia in transgenic mice.

The results suggest that the tumorigenicity of the p210bcr/abl chimeric protein is restricted to the hematopoietic tissues in vivo and that an event enhancing p210a/abl expression contributed a proliferative advantage to hematoietIC precursor cells and eventually developed T-cell leukemia in transgenic mice.

Restricted oncogenicity of BCR/ABL p190 in transgenic mice.

The results strongly suggest that the oncogenicity of BCR/ABL is limited to hematopoietic cells, including pre-B cells or their progenitors.

Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid.

Investigation of the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid found that multiple mechanisms were involved in the control ofmbn mRNA expression.

The P190, P210, and P230 Forms of the BCR/ABL Oncogene Induce a Similar Chronic Myeloid Leukemia–like Syndrome in Mice but Have Different Lymphoid Leukemogenic Activity

The hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans is not supported, and it is suggested that the rarity of P190 BCR-ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.

Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL).

Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph1-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of BCR-ABL chimeric transcripts inPh1- positive ALL cells.

BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice.

The delayed progression of BCR/ABL P210-associated disease in the transgenic mice is consistent with the apparent indolence of human chronic myeloid leukemia during the chronic phase.