PRELEUKEMIC CLONES AND THEIR IMPORTANCE TO TRANSPLANTATIONS
K. Koliakou MD, PhD Prof of Medicine
Medical Director of Biohellenika
Cancer as well as leukemia are manifested after a series of mutations which eventually result in carcinogenesis. The incidence of leukemia in children under the age of 15 is 1/2000, with the highest incidence occurring between 1-3 years. 81% of cases of leukemia in children are related to acute lymphoblastic leukemia (ALL) and from the rest of the other forms, the more frequent is Acute Myeloblastic Leukemia (AML). Although 85% of children with ALL have long-term survival, they still suffer from chronic morbidity and heart problems as complications of chemotherapy.
The probability of acute leukemia occurring in the first 15 years of an individual's life is 0.08%; 60% of children with ALL have recurrence after treatment and only 40% of them have long-term survival. Acute leukemia in children is gradually established and is due to the concentration of two continuous mutations in the hematopoietic stem cells. This type of evolution is followed by ALL. The first mutation leads to the formation of pre-leukemic clones, which are not sufficient for the appearance of leukemia. A second mutation in the same cell population leads to the onset of ALL.
The agents implicated in the appearance of the second and determinant mutation are viral infections and common pathogens that lead the cell to failing to follow the normal cell cycle. Four genes are responsible for the appearance of preleukaemic clones and their incidence is: TEL-AML1 (24-26%), E2A-PBX (5-6%), BCR-ABL (3-5%) and MLL- AF4 (5%). Pre-leukemic clones which are developed in early stages of fetal’s life affect more cell lines and more dangerous they are to develop leukemia.
Some of these clones appear initially in the primitive mesenchymal cells of the umbilical cord tissue, from which the primitive hematopoietic cells are formed, which are then migrate to the hematopoietic organs. Pre-leukemic clones remain in the bloodstream and are detected even 15 years after birth. The most common gene detected in cord blood that is related to ALL is TEL-AML1 and its incidence in the newborn population is 1%. In fact, however, the occurrence of ALL is 100 times lower, meaning that 1% of children with the TEL-AML1 mutation will eventually develop leukemia.
A significant number of healthy adults, according to some authors, the 42% and to others 74%, carry a mutation of another leukemia gene, BCR-ABL, which are currently healthy. It seems that the presence of preleukemic clones is of little importance for the development of leukemia and a better marker is the number of hematopoietic cells bearing these mutations.
The earlier appearance of the first mutation to the hematopoietic cell population the more hematopoietic stem cells are affected that means higher risk of leukemia is occurred. The late mutations occur in a particular hematopoietic cell population and a lower risk for the occurrence of leukemia exists. The frequency of pre-leukemic clones in the healthy monozygotic twin is ≈5%, and this is mainly due to the transfer of clones from one twin to the other through circulation rather than simultaneous leukemogenesis.
The surviving twin carries the pre-leukemic clone eight years after the death of the other twin and remains healthy. Umbilical cord blood has been used in recent years with increasing rates as a hematopoietic graft for the treatment of malignant diseases. Since 1980, published studies have been shown that malignancy can be transferred through allogeneic haematopoietic grafts, and it has been found in 5% of recurrences of leukemia that is transplanted via the transplant after allogeneic bone marrow transplantation. This type of leukemia is not due to actual relapse of the initial leukemia, but to new leukemia implanted through the transplant, Daniel Howard Wiseman (Biol Blood Marrow Transplant., 2011 Jun; 17 (6): 771-89).
Generally the transmitted malignancy through hematopoietic transplants ranges from 0.16% -5% and the mortality of patients from the use of these grafts is much greater. Pre leukemic clones in umbilical cord blood are found at a frequency of up to 5%, or 1 in 20 children are born with pre-leukemic clones in their blood without any indication that all these infants will develop Acute Lymphoblastic Leukemia (ALL). 1% of pre-leukemic clones persisted in the hematopoietic stem cells and result in leukemia. It is also unknown if all children with ALL had a pre-leukemic clone in the umbilical cord blood. Preleukemic clones gradually are removed from the blood by the immune system.
Pre-leukemic clones do not distinguish between public and private storage and occur at the same rate in both types of storage. Nowadays, the grafts are not examined for pre-leukemic clones in both Public and Private sector because the probability of progression to leukemia is very low and the social disruption would be too great, if examined. Public banks discretionary donor monitoring is recommended and not direct information on the resulting problem to the family.
In private storage grafts can be directly examined for the mutations and can be used safely if they do not have preleukemic clones, especially in elder children. Successful autologous umbilical cord blood stem cell transplantation in children with acute leukemia and hereditary cancers is reported in the literature.
The real reason that hematologists avoid to use autologous hematopoietic stem cells is not the fear of transplanted mutations, especially in the cases that they can check the transplant, but because autologous cord blood hematopoietic cells do not have the graft versus leukemia effect or antileukemic reaction.