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Published by: j.doe.hex_87 on May 20, 2010
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Definition: chronic granulocytic leukemia (CGL) is a clonal

malignant transformation of the stem cell, characterized by proliferation of the granulocytes which retain their capacity to differentiate.

The hallmark of the CGL is :
\u2022the presence of the Ph-chromosome;
\u2022the very low (or even zero) score of the leukocytic
alkaline phosphatase;
\u2022the presence of the all stages of the granulocytic
precursors in peripheral blood;
Synonyms: chronicmyelogenous leukemia; chronicmyeloid leukemia;
chronicmye locyt i c leukemia.
1.- Irradiation : CGL appears with a higher incidence in professional ,

therapeutical or accidental irradiated people(the median latent period seems to be 4 years in ankylosing spondylitis, 9 years in uterine cervical cancer and 11 years in Japanese atomic bombs survivors);

2.-Chemicals and drugs : the role played by certain organic solvents
(as benzene) or drugs ( cytostatics, DNA topoisomerase II inhibitors) is
3.-Genetic background : a higher incidence of the HLA antigens CW3

and CW4 has been found, suggesting thus a greater susceptibility to CGL. The disease is acquired, not inherited: children born from mothers with CGL are not affected, neither the identical twin of a patient with CGL ;

1. -incidence in the USA : 1,4/100,000 ;

2. -the higher incidence appears in the fourth and fifth decade ; the CGL is uncommon in children and accounts for less than 5% of all childhood leukemias ;

3. -a slightly higher incidence in men has been observed;
A.-at molecular level:
1. - CGL appears from the malignant transformation of a single stem cell.
Arguments for this :
the involvement of erythropoiesis, thrombopoiesis and of all of
the granulocytic lineages during the chronic phase of the CGL;

the presence of the Ph-chromosome in the precursors of the erythropoietic, granulocytic and thrombocytic precursors, in the mono-macrophagic precursors well as (sometimes) in the lymphocytic ones;


studies on isoenzymes of the glucose-6-P-dehydrogenase and on the presence of Ph-chromosome in patients who are a mosaic for sex chromosomes, as in Turner or Klinefelter syndrome;

2.-the abnormal clone coexists in the same patient with
normal stem cells;
3.-the cytogenetic hallmark of the CGL is the presence of the Ph-

chromosome. It was recognized first as a small 22 chromosome and has been denominated thus after the city where it has been discovered. Later studies demonstrated that that the Philadelphia chromosome consists in a reciprocal translocationt(9,22)(q34;q11). The break- points appears on the long-arm of the 22-chromosome, named \u201cbreak point cluster region\u201d orbcr and in a region of the long arm of the chromosome 9, where thec- abl gene is located ( c-abl is the cellular homologue of the transforming oncogene of the Abelson murine leukemia virus). The remaining sequences of the bcr-region on the 22- chromosome act as an accepter for the c-abl gene and achimeric

fusion geneABL- BCR appears , which is active: it gives rise to a

chimeric RNA-messenger and consequently to a chimeric protein, namely a new 210 kD tyrosine-kinase, which has the capacity to activate cells. But the translocation phenomenon is reciprocal, so that a piece of chromosome 22 is translocated also to the chromosome 9.

4. -the Ph-chromosome plays (with the greatest probability) the key
pathogenic role.Some arguments :
-is found in 95 % of the patients ;

-even in those patients where the Ph-chromosome could not been revealed by classical methods, the chimeric new gene bcr- abl can be detected by polymerase chain reaction

- the Ph-chromosome can be detected in the very early phase of
the CGL;

-it persists in all stages of the disease, but during the blast crisis, other chromosomal abnormalities associate (duble Ph, deletion of Y, trisomy 9, 19 or 21)

-the affected clone coexists with normal stem cells;
-in cell culture, the loss of Ph-chromosome associated with loss
of proliferative advantage;

-the effects of bcr-abl on cell adhesion reveal the loss of blocking mitosis in clones Ph-positive chromosome, which is the hallmark of a proliferative advantage;

B.-at cellular level :

1. -the transformed hematopoietic stem cell generates an increasingly expanded pool of committed stem cells for granulocytic and, at least initially, megakaryocytic and erythroid cell lines;

2.-the leukemic cells retainpartially their maturation capacity: in

peripheral blood , a continuously increasing number of neutrophils appears, as well as eosinophils and basophils; in earlier stages, because megakaryocytes are increased in bone marrow, a great number of platelets appears in peripheral blood;

3. -the leukemic cellular pool overwhelms the normal erythropoiesis and
extends to extramedullary sites;
C.-at clinical level :
1.-leukemic cells proliferate:
a.-in bone marrow :
spontaneous pain of the sternum , accentuated by
as the diseases progresses, pain appears in long
bones, especially of the lower extremities;
b.-in extramedullary sites :

in spleen, they proliferate profusely, growing out from the red pulp toward the white pulp, where progressively replace the normal lymphoid population ;

in liver, the leukemic cells proliferate within the

as the disease progresses, the leukemic cells proliferate also in lymph nodes and infiltrate diffusely or nodular other organs and systems, including the central nervous system (CNS);

2.-as result :
a.-progressively involvement of the bone marrow :
osseous pain associates with anemia, increased
tendency to infection, spontaneous bruising;
b.-involvement of extramedullary sites:
splenic and liver enlargement;
mild lymph nodes enlargement (especially in blast
nodular proliferation (\u201cgranulocytoma\u201d ) in organs
and systems, as the disease progresses;
Clinical features:
A.-for a variable period, the patient is asymptomatic ;

no splenic enlargement (or a small and painless splenic enlargement only), neither liver or other organs or systems involvement ; the diagnosis could be suggested by fortuitous laboratory investigation and confirmed by specific tests (see later);

B.- as the leukemic clone extends, appear :

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