Insights into the stem cells of CML

Insights into the stem cells of chronic myeloid leukemia by I Sloma, X Jiang, A C Eaves and C J Eaves, Leukemia 2010(Sep 23). [Epub ahead of print][PubMed citation]. Abstract:

Chronic myeloid leukemia (CML) has long served as a paradigm for generating new insights into the cellular origin, pathogenesis and improved approaches to treating many types of human cancer. Early studies of the cellular phenotypes and genotypes represented in leukemic populations obtained from CML patients established the concept of an evolving clonal disorder originating in and initially sustained by a rare, multipotent, self-maintaining hematopoietic stem cell (HSC). More recent investigations continue to support this model, while also revealing new insights into the cellular and molecular mechanisms that explain how knowledge of CML stem cells and their early differentiating progeny can predict the differing and variable features of chronic phase and blast crisis. In particular, these emphasize the need for new agents that effectively and specifically target CML stem cells to produce non-toxic, but curative therapies that do not require lifelong treatments.

Critical molecular pathways in CSCs of CML

Critical molecular pathways in cancer stem cells of chronic myeloid leukemia by Y Chen, C Peng, C Sullivan, D Li and S Li, Leukemia 2010(Sep); 24(9): 1545-54. Epub 2010 Jun 24. [Connotea bookmark][PubMed citation][Full text]. The abstract of this OA review:

Inhibition of BCR-ABL with kinase inhibitors in the treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) is highly effective in controlling but not curing the disease. This is largely due to the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for disease relapse. This stem cell resistance is not associated with the BCR-ABL kinase domain mutations resistant to kinase inhibitors. Development of curative therapies for CML requires the identification of crucial molecular pathways responsible for the survival and self-renewal of LSCs. In this review, we will discuss our current understanding of these crucial molecular pathways in LSCs and the available therapeutic strategies for targeting these stem cells in CML.

Must the last CML cell be killed?

Do we have to kill the last CML cell? DM Ross, TP Hughes and JV Melo, Leukemia 2010(Sep 16) [Epub ahead of print][FriendFeed entry][PubMed citation][Full text]. The abstract of this OA review:

Previous experience in the treatment of chronic myeloid leukaemic (CML) has shown that the achievement of clinical, morphological and cytogenetic remission does not indicate eradication of the disease. A complete molecular response (CMR; no detectable BCR-ABL mRNA) represents a deeper level of response, but even CMR is not a guarantee of elimination of the leukaemic, because the significance of CMR is determined by the detection limit of the assay that is used. Two studies of imatinib cessation in CMR are underway, cumulatively involving over 100 patients. The current estimated rate of stable CMR after stopping imatinib is approximately 40%, but the duration of follow-up is relatively short. The factors that determine relapse risk are yet to be identified. The intrinsic capacity of any residual leukaemic cells to proliferate following the withdrawal of treatment may be important, but there may also be a role for immunological suppression of the leukaemic clone. No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR-ABL-positive cells that may persist after effective therapy of CML.

Isolation and killing of candidate CML stem cells by antibody targeting

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein by Marcus Järås and 10 co-authors, including Thoas Fioretos, Proc Natl Acad Sci USA 2010(Aug 30). OA article. [Epub ahead of print][PubMed citation]. Abstract:

Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph(-)) and leukemic (Ph(+)) cells within the CML CD34(+)CD38(-) cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34(+)CD38(-)IL1RAP(+) cells were Ph(+), whereas CML CD34(+)CD38(-)IL1RAP(-) cells were almost exclusively Ph(-). By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph(+) and Ph(-) candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34(+)CD38(-) cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.

CSC news links 2010-04-18

For links to recent news items, visit these [Twitter] or [FriendFeed] pages. Examples of a few news items that have received attention:

• Split ends in CML: divergent roles of Hes1 by Catriona Jamieson, Blood 2010(Apr 8); 115(14): 2726-7 [FriendFeed entry][Connotea bookmark][PubMed citation][Full text PDF]. A comment on: Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia by Fumio Nakahara and 13 co-authors, Blood 2010(Apr 8); 115(14): 2872-81. [Epub 2009(Oct 27)][PubMed citation].


• Metabolism and the leukemic stem cell by Omar Abdel-Wahab and Ross L Levine, J Exp Med 2010(Apr 12); 207(4): 677-80 [Epub 2010(Apr 5)][FriendFeed entry][ResearchGATE entry][CiteULike entry][Connotea bookmark][PubMed citation][Full text].


• A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2alpha by Sascha Seidel and 13 co-authors, including Till Acker, Brain 2010(Apr); 133(Pt 4): 983-95 [FriendFeed entry][ResearchGATE entry][Connotea bookmark][PubMed citation].

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].

Transcriptional profiles of subsets within the CD34+ cell population in chronic phase CML

The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence by Ingmar Bruns and 16 co-authors, including Rainer Haas, Leukemia 2009(May); 23(5): 892-9 [Epub 2009(Jan 22)]. PubMed Abstract:

We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.

[Thanks to Alexey Bersenev].

Leukemic stem cells in blast crisis CML

The CML stem cell: evolution of the progenitor by Scott A Stuart, Yosuke Minami and Jean YJ Wang, Cell Cycle 2009(May 1); 8(9): 1338-43 [Epub 2009 May 17][PubMed Citation][Full text PDF (Gratis OA)].

Last paragraph of the section of full text entitled CML Stem Cells and CML Therapy:

While the differences between CSCs and cells of the bulk tumor may prevent CSCs from being eliminated by therapies that target the bulk tumor, these differences may also provide unique therapeutic targets. Therefore, the identification of cancer stem cells may open the door to new targeted therapies as the differences between the cancer stem cell, the bulk tumor, and normal cells are realized. The observation that the leukemic GMPs in CML blast crisis largely depend on the β-catenin pathway for self-renewal point to this pathway as one attractive therapeutic target. Future studies with purified populations of HSCs and GMPs from patients with CML will be essential to identifying additional differences amenable to therapeutic intervention.

[CSCs = cancer stem cells; CML = chronic myeloid leukemia; HSCs = hematopoietic stem cells; GMPs = granulocyte-macrophage progenitors].

Found via Twitter. (Thanks to Alexey Bersenev).

Inhibitory effects of omacetaxine on leukemic stem cells

Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice, by Yaoyu Chen and 5 co-authors, including Shaoguang Li, Leukemia 2009(Mar 26) [Epub ahead of print][PubMed Citation]. Examples of related news items:

Data suggesting that omacetaxine can eradicate leukemic stem cells may offer a breakthrough for CML, Physorg.com, March 26, 2009. Excerpt:

Data showing the ability of omacetaxine to kill leukemic stem cells in mouse models with drug-resistant chronic myelogenous leukemia (CML) are the subject of an advance online publication in the journal Leukemia, ChemGenex Pharmaceuticals Limited (ASX:CXS and NASDAQ:CXSP) announced today. The findings of this study provide new insights into the problem of minimal residual disease and may open the door to the development of a curative treatment strategy for some patients with CML. .....

Leukemic stem cell killer ‘omacetaxine’ help rises Chemgenex’s share, Stem Cell Research Blog, March 28, 2009. Excerpt:

ChemGenex Pharmaceuticals announced on March 26th, 2009 through online publication in the journal Leukemia, about the ability of omacetaxine to kill leukemic stem cells in mouse models with drug-resistant chronic myelogenous leukemia (CML). .....

About AML and CML

1) First Genome-Wide Expression Analysis Yields Better Understanding of Leukemia, News Release, University of Rochester Medical Center, February 10, 2009.

Genome-wide leukemia analysis completed, UPI Science News, February 11, 2009.

These news items are about the article: Dysregulated gene expression networks in human acute myelogenous leukemia stem cells by Ravindra Majeti and 9 co-authors, including Michael W Becker, Leroy Hood, Michael F Clarke and Irving L Weissman, Proc Natl Acad Sci USA 2009(Feb 13) [Epub ahead of print][PubMed Citation][Version in PMC].

2) Scientists Uncover indicator that Warns leukemia is Progressing to more dangerous form by Steve Benowitz, News Release, UC San Diego News Center, February 17, 2009.

This news release is about the article: Glycogen synthase kinase 3{beta} missplicing contributes to leukemia stem cell generation by Annelie E Abrahamsson and 15 co-authors, including Armand Keating, Robert S Negrin, Irving L Weissman and Catriona H M Jamieson, Proc Natl Acad Sci USA 2009(Feb 23) [Epub ahead of print][PubMed Citation][Full text PDF].

Elimination of CSC in a mouse model of CML

Targeting a chronic problem: elimination of cancer stem cells in CML by Claus Nerlov, EMBO J 2009(Feb 4); 28(3): 167-8 [PubMed Citation][Openly accessible full text][Version in PMC]. First paragraph:

The eradication of tumours by targeting malignant stem cell populations, or cancer stem cells (CSCs), is a promising new strategy for cancer treatment. In a paper published in a recent issue of The EMBO Journal, pharmacogenetic evidence has been obtained that this is indeed feasible in a mouse model of human chronic myeloid leukaemia. These and further similar experiments will be essential to determine the validity and practical usefulness of the CSC hypothesis.

This article is a commentary about: Cancer induction by restriction of oncogene expression to the stem cell compartment by María Pérez-Caro and 12 co-authors, including Isidro Sánchez-García, EMBO J 2009(Jan 7); 28(1): 8-20 [Epub 2008(Nov 27)][PubMed Citation][Openly accessible full text][Version in PMC]. Excerpt from the last paragraph of the Discussion section of the full text:

The data presented here further show for the first time the in vivo physiological relevance of the CSC suppression using a model system representing in vivo biology of the human CML disease. .....

CIRM videos on YouTube

There's an Announcement, dated January 20, 2009, on the home page of the California Institute for Regenerative Medicine (CIRM), entitled: CIRMTV: CIRM videos now available on YouTube. The link leads to a Playlist of CIRM Video Stem Cell Basics. One of these, Therapies Based on Cancer Stem Cells (4:33 min), features Catriona Jamieson. It currently has a 5-star rating.

For an example of a news release about the work of her group, dated April 7, 2008, see: From Bench to Bedside in One Year: Stem Cell Research Leads to Potential New Therapy for Rare Blood Disorder by Debra Kain, University of California - San Diego News Center. The first sentence:

A unique partnership between industry and academia has led to human clinical trials of a new drug for a rare class of blood diseases called myeloproliferative disorders (MPD), which are all driven by the same genetic mutation and can evolve into leukemia.

This research was funded in part by a grant from CIRM.

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