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Presents evidence for a causal relationship between the Philadelphia chromosome and human leukemia. Transgenic mice were generated for a `bcr/abl' p190 DNA construct. Methods; Results; Discussion.

In leukemia patients, resistance to drug treatment develops while the malignant cells can interact with and derive support from their microenvironment, such as bone marrow stroma. To model this process, lymphoblastic leukemia cells from BCR/ABL transgenic mice were treated with the farnesyltransferase inhibitor (FTI) SCH66336 while in coculture with primary mouse embryonic fibroblasts. Coculture with fibroblasts allowed the outgrowth of a subpopulation of drug-resistant lymphoblasts that expressed N-cadherin, a cell–cell adhesion protein that normally is only expressed on specific cell types, including hematopoietic stem cells and fibroblasts. N-cadherin expression promoted increased adhesion of the lymphoblasts to the fibroblasts. Importantly, de novo expression of N-cadherin in parental nonexpressing lymphoblasts using lentiviral transduction increased the ability of the cells to survive FTI treatment. We conclude that FTI drug treatment of Bcr/Abl-positive lymphoblastic leukemia cells that are in contact with a defined microenvironment induces the selective survival of a more primitive subpopulation of leukemia cells that expresses N-cadherin. Experimental drug treatment of cancer cells in model systems that include a microenvironment may reveal novel molecules that contribute to drug resistance and may aid in the design of specific therapies to eradicate more primitive cells.Leukemia (2007) 21, 1189–1197. doi:10.1038/sj.leu.2404667; published online 29 March 2007 [ABSTRACT FROM AUTHOR]

Precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) affects hematopoietic development and therefore is associated with immune deficiencies that can be further exacerbated by chemotherapy. It is unclear if and when monoclonal antibodies (mAbs) that stimulate antibody-mediated cellular cytotoxicity (ADCC) can be used for treatment because this depends on the presence of functional effector cells. Here, we used flow cytometry to determine that patient samples at diagnosis, post-induction and relapse contain detectable numbers of CD56+ cells. We were able to selectively expand CD56+ immune effector cells from bone marrow and peripheral blood samples at diagnosis and at various stages of treatment by co-culture with artificial antigen-presenting K562 clone 9.mbIL-21 cells. Amplified CD56+CD3− cells had spontaneous and anti-B cell-activating factor receptor mAb-stimulated ADCC activity against allogeneic ALL cells, which could be further enhanced by IL-15. Importantly, matched CD56+ effector cells also killed autologous ALL cells grown out from leukemia samples of the same patient, through both spontaneous as well as antibody-dependent cellular cytotoxicity. Since autologous cell therapy will not be complicated by graft-versus-host disease, our results show that expanded CD56+ cells could be applied for treatment of pre-B ALL without transplantation, or for purging of bone marrow in the setting of autologous bone marrow transplants. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses Galectin-3 gene in pre-B acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children and a major cause of mortality from hematopoietic malignancies in adults. A substantial number of patients become drug resistant during chemotherapy, necessitating the development of alternative modes of treatment. rGel (recombinant Gelonin)/BlyS (B-lymphocyte stimulator) is a toxin-cytokine fusion protein used for selective killing of malignant B-cells expressing receptors for B-cell-activating factor (BAFF/BLyS) by receptor-targeted delivery of the toxin, Gelonin. Here, we demonstrate that rGel/BLyS binds to ALL cells expressing BAFF receptor (BAFF-R) and upon internalization, it induces apoptosis of these cells and causes downregulation of survival genes even in the presence of stromal protection. Using an immunodeficient transplant model for human ALL, we show that rGel/BLyS prolongs survival of both Philadelphia chromosome-positive and negative ALL-bearing mice. Furthermore, we used AMD3100, a CXCR4 antagonist, to mobilize the leukemic cells protected in the bone marrow (BM) microenvironment and the combination with rGel/BLyS resulted in a significant reduction of the tumor load in the BM and complete eradication of ALL cells from the circulation. Thus, a combination treatment with the B-cell-specific fusion toxin rGel/BLyS and the mobilizing agent AMD3100 could be an effective alternative approach to chemotherapy for the treatment of primary and relapsed ALL. [ABSTRACT FROM AUTHOR]

The bone marrow (BM) stromal niche can protect acute lymphoblastic leukemia (ALL) cells against the cytotoxicity of chemotherapeutic agents and is a possible source of relapse. The stromal-derived factor-1 (SDF-1)/CXCR4 axis is a major determinant in the crosstalk between leukemic cells and BM stroma. In this study, we investigated the use of AMD11070, an orally available, small-molecule antagonist of CXCR4, as an ALL-sensitizing agent. This compound effectively blocked stromal-induced migration of human ALL cells in culture and disrupted pre-established adhesion to stroma. To examine how to optimally use this compound in vivo, several combinations with cytotoxic drugs were tested in a stromal co-culture system. The best treatment regimen was then tested in vivo. Mice transplanted with murine Bcr/Abl ALL cells survived significantly longer when treated with a combination of nilotinib and AMD11070. Similarly, immunocompromised mice transplanted with human ALL cells and treated with vincristine and AMD11070 had few circulating leukemic cells, normal spleens and reduced human CD19+ cells in the BM at the termination of the experiment. These results show that combined treatment with AMD11070 may be of significant benefit in eradicating residual leukemia cells at locations where they would otherwise be protected by stroma. [ABSTRACT FROM AUTHOR]

Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Philadelphia chromosome-positive (Ph-positive) leukemias. At a once-daily dose and a relatively short half-life of 3-5 h, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell-surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low-dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective. [ABSTRACT FROM AUTHOR]

Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity. [ABSTRACT FROM AUTHOR]

The closely related small GTP-binding proteins Rac1, Rac2, and Rac3 are part of a larger Rho subfamily of Ras proteins. Because disruption of Ras signaling pathways is relevant to the pathogenesis of a wide variety of cancers, it is important to clearly define the structural and functional characteristics of the participating proteins and their encoding genes. Rho subfamily members are involved in a range of signal transduction pathways relevant to cell growth, differentiation, motility, and stress, and Rac proteins are now recognised as a necessary component of Ras-mediated cellular transformation. We previously mapped RAC3 to chromosome band 17q23→ q25, a region that contains a number of candidate tumour suppressor genes. Because of its oncogenic potential, we have now further refined the location of this gene. Here we confirm that RAC3 maps to chromosome band 17q25.3 and further show that it maps some distance telomeric of a well-characterised minimal breast and ovarian candidate tumour suppressor gene region, BROV. The genomic structure of RAC3, including exon and intron boundaries, is also presented. Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A letter to the editor about chronic myelogenous leukemia and Ph-positive acute lymphoblastic leukemia treatment is presented.

The article presents information related to a study which demonstrates that tyrosine-phosphorylated proteins which specifically bind to the Crkl SH2 domain in the leukemic tissues of P190 BCR/ABL transgenic mice are identical to Hef1 /Cas-L. According to the study, Hef1 /Cas-L is similar to p130 Cas, except that the expression of Hef1 is limited to specific cell types within the hematopoietic lineage.