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.

Partnership Pays Off

Northern Exposure by Emmet Pierce, San Diego Business Journal, August 16, 2010. Excerpt:

An example of San Diegans collaborating with Canadians is the work that has taken place at the UC San Diego Moores Cancer Center in cooperation with research at the University of Toronto. The partnership has enabled San Diego researchers to acquire a $20 million grant to develop drugs to be used against leukemia stem cells, Barr says.Dr. Catriona Jamieson, director of the stem cell research program at the Moores center, said scientists from Toronto and San Diego share "a deep and abiding interest in cancer stem cell biology." The Canadian consulate in San Diego was instrumental in helping to create a relationship in which both institutions would benefit, sharing information and applying for funds to support their research.

"The idea was to establish a Canada-California cancer stem cell initiative and obtain connections with Canadian funding agencies, particularly Genome Canada and the Ministry of Health," she said.

Jamieson added, "The most important thing is it allows people with disparate abilities and backgrounds to work together on the same problem."

Barr said the University of Toronto also was able to secure a $20 million research grant because of the collaboration, "so the team is greater than the sum of its parts."

Review about retroviral-induced leukemogenesis and the CSC hypothesis

Hematopoietic stem cells and retroviral infection by Prabal Banerjee, Lindsey Crawford, Elizabeth Samuelson and Gerold Feuer, Retrovirology 2010(Feb 4); 7(1): 8 [Epub ahead of print][Connotea bookmark][[FriendFeed entry][PubMed Citation][Full text (PDF)].

Includes sections on Leukemia Stem Cells/Cancer Stem Cells (LSC/CSC) and on The Cancer Stem Cell Hypothesis.

SC-derived gene expression profiles predict poor outcome for AML patients

Leukemic and Normal Stem Cell Transcriptional Signatures Determined by Functional Assays Are Predictive of the Overall Survival of AML Patients by Kolja Eppert and 11 co-authors, including John E Dick, Abstract #389, 51st ASH Annual Meeting, December 7, 2009. Final sentence:

Together these data support the hypothesis that the biological determinants that underlie stemness in both normal and leukemic cells are predictors of poor outcome, and are potential targets for novel therapy.

Targeting of AML-leukemic SC with monoclonal antibodies

Targeting of AML-leukemic stem cells with monoclonal antibodies by Erwin M Lee‌ and Richard B Lock, Future Oncol 2009(Nov); 5(9): 1327-30 [PubMed Citation][FriendFeed entry][Full text PDF]. Final sentence of the full text of this Editorial:

An AML patient surface immunophenotype is relatively cost-effective to characterize, raising the prospect of individualized therapy based on a selection of available MAbs. Most certainly, we are entering a new and exciting era in the struggle to improve outcome in adult AML.

Heterogeneity in the AML stem cell pool

Heterogeneity in the AML stem cell pool by Laura E Hays, Blood 2009(Nov 5); 114(19): 3976-7 [PubMed Citation][FriendFeed entry]. Excerpt:

To examine AML and stem cell diversity, Heuser and colleagues develop a novel murine model that closely mimics aggressive human AML and demonstrate an essential role of Stat5 in leukemic stem cell renewal.

Comment on: Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal by Michael Heuser and 14 co-authors, including Gerald Krystal and R Keith Humphries, Blood 2009(Nov 5); 114(19): 3983-93 [Epub 2009(Aug 10)][PubMed Citation].

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.

Leukemia SC cloak themselves to avoid detection

Leukemia cells evade immune system by mimicking normal cells, Stanford study shows by Krista Conger, News Release, Stanford University Medical Center, July 23, 2009. First sentence:

Human leukemia stem cells escape detection by co-opting a protective molecular badge used by normal blood stem cells to migrate safely within the body, according to a pair of studies by researchers at Stanford University Medical School.

See also: Molecule Helps Leukemia Cells Hide From Immune System, Drugs.com, July 23, 2009. First sentence:

Leukemia stem cells cleverly cloak themselves to avoid detection by a person's immune system, according to a pair of studies by researchers at Stanford University Medical School.

And: Leukemia cells evade immune system by mimicking normal cells, Stanford studies show, EurekAlert, July 23, 2009.

The two articles upon which the news releases are based:

1) CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis by Siddhartha Jaiswal, Catriona H M Jamieson and 7 co-authors, including Irving L Weissman, Cell 2009(Jul 23); 138(2): 271-85. [PubMed Citation].

2) CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells by Ravindra Majeti and 7 co-authors, including Irving L Weissman, Cell 2009(Jul 23); 138(2): 286-99. [PubMed Citation][FriendFeed entry].

Targeted therapy for AML stem cells

New Targeted Therapy Finds And Eliminates Deadly Leukemia Stem Cells, ScienceDaily July 3, 2009. [FriendFeed entry]. First paragraph:

New research describes a molecular tool that shows great promise as a therapeutic for human acute myeloid leukemia (AML), a notoriously treatment-resistant blood cancer. The study, published in the July 2nd issue of the journal Cell Stem Cell, describes exciting preclinical studies in which a new therapeutic approach selectively attacks human cancer cells grown in the lab and in animal models of leukemia.

The news release is about this article: Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells by Liqing Jin and 14 co-authors, including John E Dick and Richard B Lock, Cell Stem Cell 2009(Jul 2); 5(1): 31-42. [PubMed Citation].

Alloreactive NK cells detect and target leukemic SCs

Human acute myeloid leukemia CD34+CD38– stem cells are susceptible to allorecognition and lysis by single KIR-expressing natural killer cells by Ulrich Langenkamp and 6 co-authors, including Aleksandra Wodnar-Filipowicz, Haematologica 2009(Jul 16) [Epub ahead of print][FriendFeed entry][Early version of the full text PDF]. PubMed Abstract:

The concept of tumor immunosurveillance has raised prospects for natural killer (NK) cell-based immunotherapy of human cancer. The cure of acute myeloid leukemia (AML) may depend on eradication of leukemic stem cells (LSCs), the self-renewing component of leukemia. Whether NK cells can recognize and lyse LSCs is not known. To develop strategies that effectively target AML-LSCs, we investigated anti-leukemic effects of human alloreactive single KIR(+) NK cells. NK effectors with KIR specificity mismatched with respect to HLA class I allotype of target cells effectively recognized AML-LSCs defined phenotypically as CD34(+)CD38(-), while healthy bone marrow-derived CD34(+)CD38(-) hematopoietic stem cells were spared, as demonstrated by cytotoxicity and hematopoietic colony-forming assays. The HDAC inhibitor valproic acid augmented the activating NKG2D ligand-dependent lysis of AML-CD34(+)CD38(-) LSCs. These results show that alloreactive NK cells have the potential to detect and target LSCs, and thus to improve the treatment outcome in AML.

Chemosensitization of AML

Another nail in the AML coffin by Camille N Abboud, Blood 2009(Jun 11); 113(24): 6045-6. Editorial [Full text is currently publicly accessible][PubMed Citation]. First paragraph:

In this issue of Blood, Nervi and colleagues and Zeng and colleagues independently report similar findings in both in vitro and in vivo AML models, showing chemosensitization by blocking CXCR4/CXCL12 (SDF-1{alpha}:stromal cell–derived factor 1) signaling using novel CXCR4 antagonist bicyclams, namely AMD3100 (plerixafor) and AMD3465.

Excerpt from the final paragraph:

Finally, while both reports open new avenues for overcoming in vivo drug resistance in AML, it is yet unclear whether durable complete remissions can ensue from this strategy. AML is indeed a very heterogenous disease, and successful eradication of leukemic stem/progenitor cells will require blocking multiple receptors/pathways ...

The two articles discussed in this editorial are:

1) Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100 by Bruno Nervi and 10 co-authors, including Timothy J Ley, and John F DiPersio, Blood 2009(Jun 11); 113(24): 6206-14 [Epub 2008(Dec 2)]. [PubMed Citation].

2) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML by Zhihong Zeng and 12 co-authors, Blood 2009(Jun 11); 113(24): 6215-24 [Epub 2008(Oct 27)]. [PubMed Citation][FriendFeed entry].

[Only the abstracts of these two articles are currently publicly accessible].

Therapeutic monoclonal antibody targeting of AML-LSCs

New Targeted Therapy Finds And Eliminates Deadly Leukemia Stem Cells, ScienceDaily July 3, 2009. [FriendFeed entry]. First two sentences:

New research describes a molecular tool that shows great promise as a therapeutic for human acute myeloid leukemia (AML), a notoriously treatment-resistant blood cancer. The study, published in the July 2nd issue of the journal Cell Stem Cell, describes exciting preclinical studies in which a new therapeutic approach selectively attacks human cancer cells grown in the lab and in animal models of leukemia.

This news release is about the article Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells by Liqing Jin and 14 co-authors, including John E Dick and Richard B Lock, Cell Stem Cell 2009(Jul 2); 5(1): 31-42. PubMed Abstract:

Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor alpha chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+)CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.

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].

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.

Two reports about perpetuation of leukaemias

1) Hedgehog blocker thwarts cancer stem cells, ecancermedicalscience Insider News, January 25, 2009. Excerpt:

The hedgehog signalling pathway helps to maintain leukaemia stem cells, which are the very cells that spread the disease, Tannishtha Reya and colleagues report. When a small inhibitory molecule is used to disrupt the pathway in a mouse model, the cancer stem cells become depleted.

The publication referred to is: Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia by Chen Zhao and 13 co-authors, including Catriona H Jamieson and Tannishtha Reya, Nature 2009(Jan 25) [Epub ahead of print][PubMed Citation].

Added February 10, 2009: Self-renewing blood and leukaemia cells need hedgehog by Simone Alves, Nature Reports Stem Cells, February 5, 2009.

Added February 24, 2009: Cancer stem cells: Killing hedgehog to treat CML by Emily J Chenette, Nature Reviews Cancer 2009(Mar); 9: 148-9.

2) Stalling cell division keeps leukaemia stem cells going by Monya Baker, Nature Reports Stem Cells, January 8, 2009. [The full text is publicly accessible]. The first paragraph:

To sustain disease, leukemia stem cells have to keep on dividing. To do so cells require a counterintuitive resource: a protein that keeps cells from proliferating. Work reported in Nature this month shows that, by giving cancer stem cells a chance to slow down and repair DNA damage, the protein p21, a cell-cycle inhibitor, not only helps cancer maintain itself, it helps leukemia evade therapies designed to kill rapidly dividing cells. Drugs that inhibit p21 or DNA repair, then, might help leukemia speed up and self destruct.

The publication referred to is: Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells by Andrea Viale and 13 co-authors, including Pier Giuseppe Pelicci, Nature 2009(Jan 1); 457(7225): 51-6 [PubMed Citation].

Added February 10, 2009: Regulation of leukemic stem cells self-renewal and quiescence - the role of p21 by Lei Ying, Hematopoiesis, February 8, 2009.

Published CIRM-sponsored CSC research

Found via: Stem Cell Research by CIRM Grantees:

Cancer
Mutation Revealed to Convert Blood Stem Cells to Cancer Stem Cells

CIRM-funded researcher: Wei Guo

Researchers at UC, Los Angeles discovered a series of mutations that can convert normal blood stem cells into cancer stem cells. It is believed that many types of cancer result from cancer stem cells created by such mutations. In this case the first mutation converted normal stem cells and then caused over expression of an oncogene, a cancer gene, resulting in a proliferation of leukemia stem cells and acute T-cell lymphoblastic leukemia in a mouse model. The team hopes that by studying these pathways they will find ways to block them with small molecule drugs and cure the often fatal disease. The study was published in the May 22, 2008 issue of Nature.

Related Information: Nature paper, UCLA press release, The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Funding grant summary

The published paper is: Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation by Wei Guo and 10 co-authors, including Hong Wu, Nature 2008(May 22); 453(7194): 529-33 Epub 2008 May 7. [PubMed Citation].