Imatinib refractoriness of leukemia-initiating cells

Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder by Katherine I Oravecz-Wilson and 11 co-authors, including Sean J Morrison and Theodora S Ross, Cancer Cell 2009(Aug 4); 16(2): 137-48. Last sentence of the PubMed Abstract:

Although imatinib dramatically decreased disease burden, LICs persisted, demonstrating imatinib refractoriness of LICs.

Specific target gene found using CML mouse model

Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia by Yaoyu Chen, Yiguo Hu, Haojian Zhang, Cong Peng, Shaoguang Li, Nature Genetics 2009(June 7).

For a news release about this article, see: A lethal cancer knocked down by one-two drug punch, Genetic Engineering & Biotechnology News, June 7, 2009. Excerpts:

The researchers found that CML did not develop in mice without Alox5 because of impaired function of leukemia stem cells. Also, Alox5 deficiency did not affect normal stem cell function, providing the first clear differentiation between normal and cancer stem cells.

[Shaoguang] Li also treated mice with CML with Zileuton, an asthma medication that inhibits the Alox5 inflammation pathway, as well imatinib, commonly known as Gleevec, the most effective current leukemia medication. Imatinib effectively treated CML, but Zileuton was more effective. The two drugs combined provided an even better therapeutic effect.

[Thanks to Alexey Bersenov].

Making an anti-leukemia drug better

Making an Anti-leukemia Drug Better, Ivanhoe's Medical Breakthroughs, October 21, 2008. The first sentence:

A recent discovery suggests the best way to treat leukemia may be to rely on a combination of targeted drugs rather than a single miracle drug.

The drug is imatinib.

The news item is based on: AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells by Liang L Zhou and 9 co-authors, including Xiaoyan Jiang, J Exp Med 2008(Oct 20): jem.20072316. [Epub ahead of print]. PubMed Abstract:

Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL-transduced lin(-)CD34(+) human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL-inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2-STAT5. Moreover, we identified an AHI-1-BCR-ABL-JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2-STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.

See also: Giving imatinib a hand, Amy Maxmen, J Exp Med 2008(Oct 20): jem.20511iti5