High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia.

Abstract

In BCR-ABL1(+) leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1(+) cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-β, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph(+) chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1(+) leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1(+) leukemia.

• Authors: Wolfgang Warsch, Karoline Kollmann, Eva Eckelhart, Sabine Fajmann, Sabine Cerny-Reiterer, Andrea Hölbl, Karoline V Gleixner, Michael Dworzak, Matthias Mayerhofer, Gregor Hoermann, Harald Herrmann, Christian Sillaber, Gerda Egger, Peter Valent, Richard Moriggl, Veronika Sexl
• Journal: Blood (Blood) Vol. 117 Issue 12 Pg. 3409-20 (Mar 24 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21220747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• STAT5 Transcription Factor
• Imatinib Mesylate

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Benzamides
• Cells, Cultured
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (diagnosis, drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Piperazines (therapeutic use)
• Prognosis
• Pyrimidines (therapeutic use)
• STAT5 Transcription Factor (genetics, physiology)
• Treatment Failure
• Up-Regulation (genetics, physiology)
• Xenograft Model Antitumor Assays