Genetic marker predicts which leukemia patients will relapse after treatment
Researchers have identified a molecular signature that distinguishes leukemia patients likely to relapse from those who will stay in remission. The finding could help doctors tailor treatment intensity upfront and guide development of new drugs targeting therapy-resistant disease, a leading cause of childhood cancer deaths.
Originaltitel: Increased <em>MYB</em> alternative promoter usage is associated with relapse in acute lymphoblastic leukemia
<p>Therapy-resistant disease is a major cause of death in patients with acute lymphoblastic leukemia (ALL). Activation of the <em>MYB</em> oncogene is associated with ALL and leads to uncontrolled neoplastic cell proliferation and blocked differentiation. Here, we used RNA-seq to study the clinical significance of <em>MYB</em> expression and <em>MYB</em> alternative promoter (TSS2) usage in 133 pediatric ALLs. RNA-seq revealed that all cases analyzed overexpressed <em>MYB</em> and demonstrated <em>MYB</em> TSS2 activity. qPCR analyses confirmed the expression of the alternative <em>MYB</em> promoter also in seven ALL cell lines. Notably, high <em>MYB</em> TSS2 activity was significantly associated with relapse (<em>p</em> = 0.007). Moreover, cases with high <em>MYB</em> TSS2 usage showed evidence of therapy-resistant disease with increased expression of ABC multidrug resistance transporter genes (e.g., <em>ABCA2, ABCB5</em>, and <em>ABCC10</em>) and enzymes catalyzing drug degradation (e.g., <em>CYP1A2</em>, <em>CYP2C9</em>, and <em>CYP3A5</em>). Elevated <em>MYB</em> TSS2 activity was further associated with augmented KRAS signaling (<em>p</em> < 0.05) and decreased methylation of the conventional <em>MYB</em> promoter (<em>p</em> < 0.01). Taken together, our results suggest that <em>MYB</em> alternative promoter usage is a novel potential prognostic biomarker for relapse and therapy resistance in pediatric ALL.</p>