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].

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].