The Biology of Chronic Myeloid Leukemia

doi:10.1056/NEJM199907153410306

Volume 341:164-172		July 15, 1999		Number 3

The Biology of Chronic Myeloid Leukemia

Stefan Faderl, M.D., Moshe Talpaz, M.D., Zeev Estrov, M.D., Susan O'Brien, M.D., Razelle Kurzrock, M.D., and Hagop M. Kantarjian, M.D.

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Chronic myeloid leukemia (CML) is a clonal myeloproliferativeexpansion of transformed, primitive hematopoietic progenitorcells. It involves myeloid, monocytic, erythroid, megakaryocytic,B-lymphoid, and occasionally T-lymphoid lineages.¹ CML was thefirst human disease in which a specific abnormality of the karyotype— the Philadelphia (Ph) chromosome — could be linkedto pathogenetic events of leukemogenesis.² It was among thefirst neoplastic diseases in which therapy with a biologic agent(interferon) was found to suppress the leukemic clone and prolongsurvival.³

Although heterogeneous, CML is the best-characterized leukemiaat a molecular level, and studies in recent years have helpedto define further . . . [Full Text of this Article]

Epidemiology and Clinical Characteristics

Molecular Biology

The Ph Chromosome

Pathways of BCR–ABL Signaling

The Cellular Biology of CML

Molecular and Cellular Events in Disease Transformation

Diagnosis and Monitoring of CML in Patients with BCR–ABL

Minimal Residual Disease in CML

Therapeutic Implications

Adoptive Immunotherapy and Immunomodulation

Mechanisms of Action of Interferon Alfa

Conclusions

Source Information

From the Departments of Leukemia (S.F., S.O., H.M.K.) and Bioimmunotherapy (M.T., Z.E., R.K.), University of Texas M.D. Anderson Cancer Center, Houston.

Address reprint requests to Dr. Kantarjian at the Department of Leukemia, Box 61, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.

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Gorre, M. E., Ellwood-Yen, K., Chiosis, G., Rosen, N., Sawyers, C. L. (2002). BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 100: 3041-3044 [Abstract] [Full Text]
Kantarjian, H. M., O'Brien, S., Cortes, J. E., Giralt, S. A., Rios, M. B., Shan, J., Giles, F. J., Thomas, D. A., Faderl, S., De Lima, M., Garcia-Manero, G., Champlin, R., Arlinghaus, R., Talpaz, M. (2002). Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 100: 1590-1595 [Abstract] [Full Text]
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Nilsson, L., Astrand-Grundstrom, I., Anderson, K., Arvidsson, I., Hokland, P., Bryder, D., Kjeldsen, L., Johansson, B., Hellstrom-Lindberg, E., Hast, R., Jacobsen, S. E. W. (2002). Involvement and functional impairment of the CD34+CD38-Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8. Blood 100: 259-267 [Abstract] [Full Text]
Cohen, M. H., Williams, G., Johnson, J. R., Duan, J., Gobburu, J., Rahman, A., Benson, K., Leighton, J., Kim, S. K., Wood, R., Rothmann, M., Chen, G., U, K. M., Staten, A. M., Pazdur, R. (2002). Approval Summary for Imatinib Mesylate Capsules in the Treatment of Chronic Myelogenous Leukemia. Clin. Cancer Res. 8: 935-942 [Abstract] [Full Text]
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Glei{beta}ner, B., Gokbuget, N., Bartram, C. R., Janssen, B., Rieder, H., Janssen, J. W. G., Fonatsch, C., Heyll, A., Voliotis, D., Beck, J., Lipp, T., Munzert, G., Maurer, J., Hoelzer, D., Thiel, E., German Multicenter Trials of Adult Acute Lymphobla, (2002). Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 99: 1536-1543 [Abstract] [Full Text]
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Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M., Lydon, N. B., Kantarjian, H., Capdeville, R., Ohno-Jones, S., Sawyers, C. L. (2001). Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. NEJM 344: 1031-1037 [Abstract] [Full Text]
Druker, B. J., Sawyers, C. L., Kantarjian, H., Resta, D. J., Reese, S. F., Ford, J. M., Capdeville, R., Talpaz, M. (2001). Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome. NEJM 344: 1038-1042 [Abstract] [Full Text]
Deutsch, E., Dugray, A., AbdulKarim, B., Marangoni, E., Maggiorella, L., Vaganay, S., M'Kacher, R., Rasy, S. D., Eschwege, F., Vainchenker, W., Turhan, A. G., Bourhis, J. (2001). BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood 97: 2084-2090 [Abstract] [Full Text]
Li, S., Gillessen, S., Tomasson, M. H., Dranoff, G., Gilliland, D. G., Van Etten, R. A. (2001). Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL. Blood 97: 1442-1450 [Abstract] [Full Text]
Zhang, X., Subrahmanyam, R., Wong, R., Gross, A. W., Ren, R. (2001). The NH2-Terminal Coiled-Coil Domain and Tyrosine 177 Play Important Roles in Induction of a Myeloproliferative Disease in Mice by Bcr-Abl. Mol. Cell. Biol. 21: 840-853 [Abstract] [Full Text]
Zhang, X., Wong, R., Hao, S. X., Pear, W. S., Ren, R. (2001). The SH2 domain of Bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype. Blood 97: 277-287 [Abstract] [Full Text]
Thiesing, J. T., Ohno-Jones, S., Kolibaba, K. S., Druker, B. J. (2000). Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood 96: 3195-3199 [Abstract] [Full Text]
Nilsson, L., Astrand-Grundstrom, I., Arvidsson, I., Jacobsson, B., Hellstrom-Lindberg, E., Hast, R., Jacobsen, S. E. W. (2000). Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood 96: 2012-2021 [Abstract] [Full Text]
Reuter, C. W. M., Morgan, M. A., Bergmann, L. (2000). Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?. Blood 96: 1655-1669 [Abstract] [Full Text]
Krystal, G. W., Honsawek, S., Litz, J., Buchdunger, E. (2000). The Selective Tyrosine Kinase Inhibitor STI571 Inhibits Small Cell Lung Cancer Growth. Clin. Cancer Res. 6: 3319-3326 [Abstract] [Full Text]
Puccetti, E., Güller, S., Orleth, A., Brüggenolte, N., Hoelzer, D., Ottmann, O. G., Ruthardt, M. (2000). BCR-ABL Mediates Arsenic Trioxide-induced Apoptosis Independently of Its Aberrant Kinase Activity. Cancer Res. 60: 3409-3413 [Abstract] [Full Text]
Reuben, J. M., Lee, B.-N., Johnson, H., Fritsche, H., Kantarjian, H. M., Talpaz, M. (2000). Restoration of Th1 Cytokine Synthesis by T Cells of Patients with Chronic Myelogenous Leukemia in Cytogenetic and Hematologic Remission with Interferon-{{alpha}}. Clin. Cancer Res. 6: 1671-1677 [Abstract] [Full Text]
Era, T., Witte, O. N. (2000). Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate. Proc. Natl. Acad. Sci. USA 97: 1737-1742 [Abstract] [Full Text]
Parada, Y., Banerji, L., Glassford, J., Lea, N. C., Collado, M., Rivas, C., Lewis, J. L., Gordon, M. Y., Thomas, N. S. B., Lam, E. W.-F. (2001). BCR-ABL and Interleukin 3 Promote Haematopoietic Cell Proliferation and Survival through Modulation of Cyclin D2 and p27Kip1 Expression. J. Biol. Chem. 276: 23572-23580 [Abstract] [Full Text]
Kourlas, P. J., Strout, M. P., Becknell, B., Veronese, M. L., Croce, C. M., Theil, K. S., Krahe, R., Ruutu, T., Knuutila, S., Bloomfield, C. D., Caligiuri, M. A. (2000). Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: Evidence for its fusion with MLL in acute myeloid leukemia. Proc. Natl. Acad. Sci. USA 97: 2145-2150 [Abstract] [Full Text]

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