PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia

Abstract

<p class="first" id="P4">Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL, incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription factor gene <i>PAX5</i>. One, PAX5alt (7.4%), has diverse <i>PAX5</i> alterations (rearrangements, intragenic amplifications or mutations), and a second subtype is defined by PAX5 p.Pro80Arg and biallelic <i>PAX5</i> alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic <i>Pax5</i> alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. </p>