Expression of p16^INK4A and p14^ARF in hematological malignancies

Abstract

The INK4A/ARF locus yields two tumor suppressors, p16^INK4A and p14^ARF, and is frequently deleted in human tumors. We studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used a quantitative reverse transcription-PCR assay. Normal peripheral bloods, bone marrow and lymph nodes expressed little or undetectable p16^INK4A and p14^ARF mRNAs, which were readily detected in 12 and 17 of 41 cell lines, respectively. Patients with hematological malignancies frequently lacked p16^INK4A expression (60/137) and lost p14^ARF expression less frequently (19/137, 13.9%). Almost all patients without p14^ARF expression lacked p16^INK4A expression, which may correspond to deletions of the INK4A/ARF locus. Undetectable p16^INK4A expression with p14^ARFexpression in 41 patients may correspond to p16^INK4A promoter methylation or to normal expression status of the p16^INK4A gene. All patients with follicular lymphoma (FL), myeloma or acute myeloid leukemia (AML) expressed p14^ARF while nine of 23 patients with diffuse large B cell lymphoma (DLBCL) lost p14^ARF expression. Patients with ALL, AML or blast crisis of chronic myelogenous leukemia expressed abundant p16^INK4A mRNAs more frequently than patients with other diseases (12/33 vs 6/104, P < 0.01). patients with fl and high p14^ARF expression had a significantly shorter survival time while survival for patients with DLBCL and increased p14^ARFexpression tended to be longer. These observations indicate that p16^INK4A and p14^ARF expression is differentially affected among hemato- logical malignancies and that not only inactivation but also increased expression may have clinical significance.