Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease of childhood, accounting for 2-5% of cases. There are two main types of chronic myeloid leukemia:

• Adult type (Ph1 positive)
• Juvenile type (JMML)

These diseases, in early phase, are associated with an increased number of mature cells in the blood. There is a sequential orderly maturation of cells of myeloid lineage. JMML is characterized by monocytosis and this helps differentiate it from the adult type of CML.

Adult-Type Chronic Myelogenous Leukemia (Ph1 positive)

• The presence of the Philadelphia (Ph1) chromosome
• Involvement of the myeloid, erythroid, megakaryocytic, B-, and sometimes T-lymphoid elements in the disease process.
• A biphasic (chronic and blastic phase) or triphasic clinical course.

The chronic phase with a massive accumulation of granulocyte elements at all stages responds relatively easily to cytoreductive therapy. The phase lasts for months to years. Virtually all patients with CML (chronic, accelerated, and blastic phase) eventually develop an acute (blastic) phase, relatively resistant to therapy.

Pathology

The Ph1 chromosome is the result of breaks on chromosomes 9 and 22, with a reciprocal translocation involving the distal genetic material on chromosomes 9 and 22 designated as t (9;22) (q34;q11).

As a consequence of this translocation, the c-abl proto-oncogene is transposed from its normal position on chromosome 9 to a new position on chromosome 22, adjacent to the breakpoint cluster region (bcr) of the BCR gene. With juxtaposition of c-abl to the bcr region, a new fusion (chimeric) bcr / abl oncogene is formed. The bcr / abl gene encodes a 210-kDa protein, which, through its properties of increased tyrosine kinase activity and ability to autophosphorylate, changes normal hematopoietic cells into CML cells.

CML cells express the transmembrane cellular adhesion molecules but lack expression of the phosphotidyl inositol glycan anchor. This results in reduced adherence and decreased interaction of the CML cells to the stromal matrix of the bone marrow. Consequently, CML cells remain in the late progenitor phase for a longer time before differentiation. Reduced adherence also leads to the release of immature CML cells into the circulation and facilitates extramedullary hematopoiesis. Even though the CML progenitor cells divide more slowly than normal hematopoietic progenitor cells, they are capable of producing CFU-GM in excessive quantities, which results in hyperproduction of myeloid cells in CML. The average half-life of CML granulocytes is 5-10 times longer than normal granulocytes. This suggests that the CML cells may live longer by not undergoing programmed cell death (apoptosis).

CML cells may derive their growth advantage by modifications of feedback regulatory pathways of myelopoiesis such as (1) deficient lactoferrin production by polymorphonuclear cells and (2) decreased sensitivity of progenitor cells to prostaglandin E and acidic isoferritins because of a deficiency of HLA-DR antigen expression on their cell surface.