Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001

Thai Hoa Tran, Sylvie Langlois, Caroline Meloche, Maxime Caron, Pascal Saint-Onge, Alexandre Rouette, Alain R. Bataille, Camille Jimenez-Cortes, Thomas Sontag, Henrique Bittencourt, Caroline Laverdière, Vincent Philippe Lavallée, Jean Marie Leclerc, Peter D. Cole, Lisa M. Gennarini, Justine M. Kahn, Kara M. Kelly, Bruno Michon, Raoul Santiago, Kristen E. StevensonJennifer J.G. Welch, Kaitlin M. Schroeder, Victoria Koch, Sonia Cellot, Lewis B. Silverman, Daniel Sinnett

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n 5 36), ETV6-RUNX1/-like (n 5 31), TCF3-PBX1 (n 5 7), KMT2A-rearranged (KMT2A-R; n 5 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n 5 1), hypodiploid (n 5 1), Philadelphia chromosome (Ph)-positive/Ph-like (n 5 16), DUX4-R (n 5 11), PAX5 alterations (PAX5 alt; n 5 11), PAX5 P80R (n 5 1), ZNF384-R (n 5 4), NUTM1-R (n 5 1), MEF2D-R (n 5 1), and others (n 5 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials.

Original languageEnglish (US)
Pages (from-to)1329-1341
Number of pages13
JournalBlood Advances
Issue number4
StatePublished - Feb 22 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hematology


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