Chronic myelogenous leukemia (CML) is a malignant disorder of the human hematopoietic stem cell<sup>95 Fialkow P.J., Jacobson R.J., Papayannopoulou T.H. Chronic myelocytic leukemia: Clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage Am J Med 1977 ;  63 : 125-130  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> characterized by the Philadelphia chromosome (Ph).<sup>195 Nowell P.C., Hungerford D.A. A minute chromosome in human chronic granulocytic leukemia Science 1960 ;  132 : 1497

Cliccare qui per andare alla sezione Riferimenti, 222 Rowley J.D. A new consistent chromosome abnormality in chronic myelogenous leukemia Nature 1973 ;  243 : 209-291

Cliccare qui per andare alla sezione Riferimenti</sup> The disease manifests itself in the initial chronic phase by an abnormal expansion of myeloid, erythroid, and megakaryocytic progenitors in the marrow, which traffic abnormally and accumulate in the peripheral blood and extramedullary locations, such as the spleen.<sup>58 Cortes J.E., Talpaz M., Kantarjian H. Chronic myelogenous leukemia: A review Am J Med 1996 ;  100 : 555-570  [inter-ref]

Cliccare qui per andare alla sezione Riferimenti, 137 Kantarjian H.M., Smith T.L., McCredie K.B. , e al. Chronic myelogenous leukemia: A multivariate analysis of the associations of patient characteristics and therapy with survival Blood 1985 ;  66 : 1326

Cliccare qui per andare alla sezione Riferimenti</sup> In addition, myeloid precursors and mature granulocytic elements are massively increased in marrow and blood.<sup>90 Eaves A.C., Eaves C.J. Abnormalities in the erythroid compartment in patients with chronic myeloid leukemia Exp Haematol 1977 ;  7 : 65-75

Cliccare qui per andare alla sezione Riferimenti, 104 Goldman J.M., Shiota F., Th'ng K.H., Orchard K.H. Circulating granulocytic and erythroid progenitor cells in chronic granulocytic leukemia Br J Haematol 1980 ;  46 : 7-13

Cliccare qui per andare alla sezione Riferimenti</sup> In some patients, increases in megakaryocytes and platelets are seen; however, the mature erythroid compartment is not expanded and the lymphoid compartment does not seem to be functionally affected. After 3 to 5 years, the disease transforms, leading to a myeloid blast crisis in approximately two thirds of patients and to a B-lymphoid and less frequently T-lymphoid blast crisis in the remaining patients.<sup>40 Canellos G.P. Clinical characteristics of the blast phase of chronic myelogenous leukemia Hematol Oncol Clin North Am 1990 ;  4 : 359

Cliccare qui per andare alla sezione Riferimenti</sup> There is ample evidence that presumed normal, polyclonal hematopoiesis coexists with the malignant Ph⁺ clone.<sup>10 Barnett M.J., Eaves C.J., Phillips G.L. , e al. Successful autografting in chronic myeloid leukaemia after maintenance of marrow in culture Bone Marrow Transpl 1989 ;  4 : 345-351

Cliccare qui per andare alla sezione Riferimenti, 61 Coulombel L., Kalousek D.K., Eaves C.J. , e al. Long-term marrow culture reveals chromosomally normal hematopoietic progenitor cells in patients with Philadelphia chromosome–positive chronic myelogenous leukemia N Engl J Med 1983 ;  308 : 1493-1498  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 172 McGlave P.B., DeFabritiis P., Deisseroth A. , e al. Autologous transplant therapy for chronic myelogenous leukemia prolongs survival: Results from eight transplant centers Lancet 1994 ;  343 : 1486-1488  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 183 Mughal T., Hoyle C., Goldman J.M. Autografting for patients with chronic myeloid leukemia—the Hammersmith experience Stem Cells 1993 ;  11 (suppl 3) : 20-22  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 215 Reiffers J., Goldman J., Meloni G. , e al. Autologous stem cell transplantation in chronic myelogenous leukemia: A retrospective analysis of the European Group for Bone Marrow Transplantation. Chronic Leukemia Working Party of the EBMT Bone Marrow Transplant 1994 ;  14 : 407

Cliccare qui per andare alla sezione Riferimenti, 265 Takahira H., Ideguchi H., Hirata J. , e al. Appearance of chromosomally normal hemopoiesis during busulfan-induced remission in a case of Ph1 positive chronic myelogenous leukemia Rinsho Ketsueki 1989 ;  30 : 251-255

Cliccare qui per andare alla sezione Riferimenti, 267 Talpaz M., Kantarjian H., Kurzrock R. , e al. Interferon-alpha produces sustained cytogenetic response in chronic myelogenous leukemia. Philadelphia chromosome–positive patients Ann Intern Med 1991 ;  114 : 532-538

Cliccare qui per andare alla sezione Riferimenti, 291 Verfaillie C.M., Mille W.J., Boyland K., McGlave P.B. Selection of benign primitive hematopoietic progenitors in chronic myelogenous leukemia on the basis of HLA-DR antigen expression Blood 1992 ;  79 : 1003-1011

Cliccare qui per andare alla sezione Riferimenti</sup> The normal Ph⁻ clone progressively decreases in size when the disease advances. Even during the initial chronic phase, the growth of the normal hematopoietic progenitors and cells is inhibited, which leads to the detection of almost exclusively Ph⁺ progenitors even at diagnosis.

The Philadelphia chromosome is the result of a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of a hybrid BCR-ABL gene on chromosome 22<sup>11 Bartram C.R., deKlein A., Hagemeijer A. , e al. Translocation of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukemia Nature 1983 ;  306 : 277-280  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 16 Ben-Neriah Y., Daley G.Q., Mes-Masson A.M. , e al. The chronic myelogenous leukemia–specific P210 protein is the product of the bcr/abl hybrid gene Science 1986 ;  233 : 212-215

Cliccare qui per andare alla sezione Riferimenti, 222 Rowley J.D. A new consistent chromosome abnormality in chronic myelogenous leukemia Nature 1973 ;  243 : 209-291

Cliccare qui per andare alla sezione Riferimenti</sup> and the reciprocal ABL-BCR gene on chromosome 9.<sup>77 Diamond J., Goldman J.M., Melo J.V. BCR-ABL, ABL-BCR, BCR, and ABL genes are all expressed in individual granulocyte-macrophage colony-forming unit colonies derived from blood of patients with chronic myeloid leukemia Blood 1995 ;  85 : 2171-2175

Cliccare qui per andare alla sezione Riferimenti, 177 Melo J.V., Gordon D.E., Cross N.C. , e al. The ABL-BCR fusion gene is expressed in chronic myeloid leukemia Blood 1993 ;  81 : 158

Cliccare qui per andare alla sezione Riferimenti, 178 Melo J.V. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype Blood 1996 ;  88 : 2375

Cliccare qui per andare alla sezione Riferimenti</sup> The BCR-ABL gene encodes for a fusion protein with elevated and disregulated tyrosine kinase activity. Several in vitro and in vivo studies demonstrate that presence of this oncoprotein is necessary and sufficient for transformation. BCR-ABL cDNA introduced in hematopoietic cell lines causes growth factor–independent growth in vitro and tumorigenicity in vivo.<sup>44 Carlesso N., Griffin J.D., Druker B.J. Use of a temperature sensitive mutant to define biological effects of the p210BCR-ABL tyrosine kinase on proliferation of a factor dependent murine cell line Oncogene 1994 ;  9 : 149

Cliccare qui per andare alla sezione Riferimenti, 64 Daley G.Q., Baltimore D. Transformation of an interleukin 3–dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein Proc Natl Acad Sci USA 1988 ;  85 : 9312  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 102 Gishizky M.L., Witte O.N. Initiation of dysregulated growth of multipotent progenitor cells by bcr-abl in vitro Science 1992 ;  256 : 836

Cliccare qui per andare alla sezione Riferimenti, 249 Sirard C., Laneuville P., Dick J.E. Expression of bcr-abl abrogates factor-dependent growth of human hematopoietic M07E cells by an autocrine mechanism Blood 1994 ;  83 : 1575-1585

Cliccare qui per andare alla sezione Riferimenti</sup> Transplantation of murine stem cells transduced with BCR-ABL cDNA causes a CML-like syndrome.<sup>65 Daley G.Q., Van Etten R.A., Baltimore D. Blast crisis in a murine model of chronic myelogenous leukemia Proc Natl Acad Sci USA 1991 ;  88 : 11335  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 66 Daley G.Q., Van Etten R.A., Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210BCR-ABL gene of the Philadelphia chromosome Science 1990 ;  247 : 824-829

Cliccare qui per andare alla sezione Riferimenti, 101 Gishizky M.L., Johnson-White J., Witte O.N. Efficient transplantation of BCR-ABL–induced chronic myelogenous leukemia-like syndrome in mice Proc Natl Acad Sci USA 1993 ;  90 : 3755  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Even though the BCR-ABL fusion gene is probably one of the oncogenes that has been most extensively studied, it is still not completely clear how BCR-ABL causes the characteristic features of CML. This article discusses briefly the molecular consequences of the BCR-ABL fusion gene, which has been discussed at length elsewhere.<sup>1 Afar D.E., Goga A., Cohen L. , e al. Genetic approaches to defining signaling by the CML-associated tyrosine kinase BCR-ABL Cold Spring Harb Symp Quant Biol 1994 ;  59 : 589

Cliccare qui per andare alla sezione Riferimenti, 146 Laneuville P. Abl tyrosine protein kinase Semin Immunol 1995 ;  7 : 255

Cliccare qui per andare alla sezione Riferimenti, 234 Sawyers C.L. Molecular consequences of the BCR-ABL translocation in chronic myelogenous leukemia Leuk Lymphoma 1993 ;  11 (suppl 2) : 101-103  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 269 Tauchi T., Broxmeyer H.E. BCR/ABL signal transduction Int J Hematol 1995 ;  61 : 105-112  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> It then reviews the current evidence to support the notion that CML in its chronic phase is a clonal hematopoietic stem cell disease in which malignant hematopoietic stem and progenitor cells respond to “normal” external proliferation and differentiation stimuli, but in which such responses are altered owing to defects in the stem and progenitor cells as a result of the BCR-ABL oncogene.