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Modulation of Philadelphia Chromosome-Positive Hematological Malignancies by the Bone Marrow Microenvironment

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Cancer Genome and Tumor Microenvironment

Part of the book series: Cancer Genetics ((CANGENETICS))

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Abstract

Hematological malignancies often have cytogenetically distinct chromosomal translocations, resulting in fusion proteins that lead to deregulation of specific signaling pathways and distinct phenotypic outcomes. The constitutively active Bcr-Abl kinase defines the underlying cause for several forms of leukemia in humans. Due to different breakpoints in the Bcr gene, the reciprocal translocation between chromosomes 9 and 22 (the so-called Philadelphia chromosome (Ph+) (Nowell, 2007; Koretzky, 2007)) generates proto-oncoproteins of variable size. The p210 Bcr-Abl fusion protein is predominantly associated with CML during the chronic phase, but can also be detected in acute lymphoblastic leukemia (ALL) during blast transformation. In contrast, the p185 Bcr-Abl fusion protein is most often associated with the generation of de novo B-lineage ALL, but also has been shown to be expressed in rare cases of T-cell ALL, mast cell ALL, as well as in endothelial cells derived from patients with CML. While high, constitutive Abl kinase activity is thought to be the driving force in initiation and progression of leukemic disease, the bone marrow microenvironment also plays a pivotal role in maintaining Ph+ leukemic stem cells. In the following chapter we discuss the interplay between expression of the Bcr-Abl fusion protein and bone marrow microenvironment-derived cues and their collective influence on leukemogenesis.

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Acknowledgments

Supported by the National Institutes of Health Grant No. R01HL056888 (LFG), R01CA134573 (LFG), and P20 RR016440 (LFG). The authors thank Ms. Stephanie Rellick for critical reading of the manuscript and Dr. Brett Hall for contributing to artwork shown in Fig. 18.1.

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  1. Department of Tissue Morphogenesis, Max-Planck Institute for Molecular Biomedicine, 48149, Münster, Germany

    Lin Wang

  2. Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV, USA

    Heather O’Leary & Laura F. Gibson

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  1. Children's Hospital of Philadelphia, Civic Center Blvd. 3615, Philadelphia, 19104, U.S.A.

    Andrei Thomas-Tikhonenko

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Wang, L., O’Leary, H., Gibson, L.F. (2010). Modulation of Philadelphia Chromosome-Positive Hematological Malignancies by the Bone Marrow Microenvironment. In: Thomas-Tikhonenko, A. (eds) Cancer Genome and Tumor Microenvironment. Cancer Genetics. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0711-0_18

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