Myeloproliferative disease in transgenic mice expressing P230 Bcr/Abl: longer disease latency, thrombocytosis, and mild leukocytosis

Inokuchi, Koiti; Dan, Kazuo; Takatori, Miyuki; Takahuji, Hidemasa; Uchida, Naoya; Inami, Mitsuharu; Miyake, Keisuke; Honda, Hiroaki; Hirai, Hisamaru; Shimada, Takashi

doi:10.1182/blood-2002-10-3182

Cited by 23 publications

(6 citation statements)

References 20 publications

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“…An association with e19a2 BCR-ABL1 transcripts in CML patients and marked thrombocytosis has previously been documented [14], corroborated by the characterisation of a distinctive high platelet count in a transgenic mouse model expressing p230 BCR-ABL1 [16], and supported by the findings in the patient described herein. As to whether the significant thrombocytosis contributed to the DVT in this patient remains unknown: a prompt targeted reduction in platelets may be warranted in such cases to reduce the risk of thrombosis.…”

Section: Discussionsupporting

confidence: 82%

Chronic Myeloid Leukemia with e19a2BCR-ABL1Transcripts and Marked Thrombocytosis: The Role of Molecular Monitoring

Langabeer

McCarron

Kelly

et al. 2012

Case Reports in Hematology

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While most patients with chronic myeloid leukemia (CML) express either e13a2 or e14a2BCR-ABL1transcripts, a significant minority expresses variant transcripts, of which e19a2 is the most common. Although considered to have a relatively favourable outcome, reported responses to tyrosine kinase inhibitor (TKI) therapy are variable with molecular monitoring in CML patients with e19a2BCR-ABL1transcripts rarely reported. A case of e19a2BCR-ABL1CML with marked thrombocytosis is described in which the value of molecular monitoring is emphasised during treatment interruptions, dose reductions, and changes. This case serves to demonstrate the requirement for prospective real-time quantitative PCR (RQ-PCR) assays for patients with variantBCR-ABL1transcript types and standardisation of such assays to enable modern patient management.

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Section: Discussionsupporting

confidence: 82%

Chronic Myeloid Leukemia with e19a2BCR-ABL1Transcripts and Marked Thrombocytosis: The Role of Molecular Monitoring

Langabeer

McCarron

Kelly

et al. 2012

Case Reports in Hematology

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“…This milder and more megakaryocytic phenotype observed in some mice is reminiscent of other murine transplant models for MPD42 or BCR/ABL transgenic mice43,44 where lower levels of STAT5 activation were associated with large populations of megakaryocytes. Phospho-STAT5 dosage controls erythroid versus megakaryocyte differentiation45 and may explain differences in pathophysiology observed in MPD mouse models.…”

Section: Discussionmentioning

confidence: 62%

STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease

Miskimen

Wang

et al. 2010

Blood

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Phosphorylated signal transducer and activator of transcription 5 (STAT5) is a biomarker and potential molecular target for hematologic malignancies. We have shown previously that lethal myeloproliferative disease (MPD) in mice mediated by persistently activated STAT5 (STAT5aS711F) requires the N-domain, but the mechanism was not defined. We now demonstrate by retrovirally complementing STAT5abnull/null primary mast cells that relative to wild-type STAT5a, STAT5a lacking the N-domain (STAT5aΔN) ineffectively protected against cytokine withdrawal-induced cell death. Both STAT5a and STAT5aΔN bound to a site in the bcl-2 gene and both bound near the microRNA 15b/16 cluster. However, only STAT5a could effectively induce bcl-2 mRNA and reciprocally suppress miR15b/16 leading to maintained bcl-2 protein levels. After retroviral complementation of STAT5abnull/null fetal liver cells and transplantation, persistently active STAT5aS711F lacking the N-domain (STAT5aΔNS711F) was insufficient to protect c-Kit+Lin−Sca-1+ (KLS) cells from apoptosis and unable to induce bcl-2 expression, whereas STAT5aS711F caused robust KLS cell expansion, induction of bcl-2, and lethal MPD. Severe attenuation of MPD by STAT5aΔNS711F was reversed by H2k/bcl-2 transgenic expression. Overall, these studies define N-domain–dependent survival signaling as an Achilles heel of persistent STAT5 activation and highlight the potential therapeutic importance of targeting STAT5 N-domain–mediated regulation of bcl-2 family members.

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“…17 The progression of the disease in this murine model is similar to that of human neutrophilic myelogenous leukemia or chronic myelogenous leukemia with thrombocytosis. Reports have shown that BM microvessel density and serum VEGF are important for the development and prognosis of MPD.…”

mentioning

confidence: 60%

Antiangiogenic gene therapy of myeloproliferative disease developed in transgenic mice expressing P230 bcr/abl

et al. 2004

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Antiangiogenic gene therapy offers an attractive approach to the treatment of a variety of malignancies, including those of the hematological system. However, evaluation of this approach has been hampered by the lack of appropriate animal models. We have recently produced transgenic mice expressing P230 bcr/abl that develop myeloproliferative disease (MPD) closely resembling human chronic myelogenous leukemia. Using this MPD murine model, we examined the feasibility of systemic antiangiogenic gene therapy for hematological malignancy. An adenoviral vector containing the secretable endostatin gene was injected into the right quadriceps muscle of the MPD mice. The increased endostatin level was detected for at least 6 months. Hematological parameters including platelet counts, granulocyte counts, and the hemoglobin concentration were improved by this gene therapy. Infiltration of megakaryocytes was also significantly inhibited in treated MPD mice. Reduction of the microvessel density was confirmed by histological examination. These results demonstrated, for the first time, that antiangiogenic gene therapy is effective to inhibit leukemogenesis caused by expression of the chimeric bcr/abl gene. Gene Therapy (2005) 12, 541-545.

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Myeloproliferative disease in transgenic mice expressing P230 Bcr/Abl: longer disease latency, thrombocytosis, and mild leukocytosis

Cited by 23 publications

References 20 publications

Chronic Myeloid Leukemia with e19a2BCR-ABL1Transcripts and Marked Thrombocytosis: The Role of Molecular Monitoring

Chronic Myeloid Leukemia with e19a2BCR-ABL1Transcripts and Marked Thrombocytosis: The Role of Molecular Monitoring

STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease

Antiangiogenic gene therapy of myeloproliferative disease developed in transgenic mice expressing P230 bcr/abl

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