P15 and P16 Gene Deletions and Their Relation to Elevated Levels of Dihydrofolate Reductase (DHFR) In Childhood Acute Lymphoblastic Leukemia (ALL)
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Recent studies showed over-expression of the enzyme dihydrofolate reductase (DHFR) in some patients of acute lymphoblastic leukemia (ALL) (Matherly et al., 1997). This suggests inherent resistance to normal doses of the chemotherapeutic agent methotrexate (mtx) for which DHFR is a target. Therefore, finding biological markers of DHFR over-expression could be useful in improving treatment strategies. Using Southern blotting techniques we assayed B-precursor ALL and T-cell ALL DNA samples for the deletIons of two genes, p 15 ink4B and p 16 ink4A . Flow cytometry with the fluorescent methotrexate analog PT430 was used to measure DHFR levels in blasts from the same patients. Eighteen percent of the B-precursor samples had homozygous deletions of p 15 ink4B and p 16 ink4A or p 15 ink4B alone. One hundred percent of this fractIon showed elevated levels of DHFR while 68% of the samples with both genes intact showed elevated levels of DHFR. Fifty-three percent of the T-cell ALL specimens had homozygous deletions of p 15 ink4B and p 16 ink4A or p 16 ink4A alone. Eighty-eIght percent of the specimens with these deletions was characterized by high levels of DHFR as opposed to 64% of the specimens with both genes intact. These results suggest that, while the deletion of these two tumor suppressor genes may have a role in DHFR over-expression, there are probably other factors involved.