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lecture2b-cgl(detailed)

lecture2b-cgl(detailed)

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08/05/2014

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CHRONIC GRANULOCYTIC LEUKEMIA
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;
\u2022splenomegaly
Synonyms: chronicmyelogenous leukemia; chronicmyeloid leukemia;
chronicmye locyt i c leukemia.
Etiology:
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
controversial;
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 ;

Epidemiology:
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;
Pathogenesis:
A.-at molecular level:
1. - CGL appears from the malignant transformation of a single stem cell.
Arguments for this :
\u2022
the involvement of erythropoiesis, thrombopoiesis and of all of
the granulocytic lineages during the chronic phase of the CGL;
\u2022

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;

\u2022

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 :
\u2022
-is found in 95 % of the patients ;
\u2022

-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

\u2022
- the Ph-chromosome can be detected in the very early phase of
the CGL;
\u2022

-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)

\u2022
-the affected clone coexists with normal stem cells;
\u2022
-in cell culture, the loss of Ph-chromosome associated with loss
of proliferative advantage;
\u2022

-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 :
\u2022
spontaneous pain of the sternum , accentuated by
palpation;
\u2022
as the diseases progresses, pain appears in long
bones, especially of the lower extremities;
b.-in extramedullary sites :
\u2022

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

\u2022
in liver, the leukemic cells proliferate within the
sinusoids;
\u2022

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 :
\u2022
osseous pain associates with anemia, increased
tendency to infection, spontaneous bruising;
b.-involvement of extramedullary sites:
\u2022
splenic and liver enlargement;
\u2022
mild lymph nodes enlargement (especially in blast
crisis);
\u2022
nodular proliferation (\u201cgranulocytoma\u201d ) in organs
and systems, as the disease progresses;
Clinical features:
A.-for a variable period, the patient is asymptomatic ;
\u2022

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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