Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia

Abstract

Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in paediatric and adult AML.

Comment on: Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia

“…One possibility is that chemotherapy resistance is linked to transcriptional programmes that are either established in the cell of origin or acquired de novo during transformation, independently of specific somatic mutations. Consistent with this hypothesis, Brown et al (2016) identified several genes that were expressed more highly in diagnostic specimens from patients who failed induction as compared to those that achieved a remission. Similarly, Stavropoulou et al (2016) and Krivtsov et al (2013) have shown that KMT2A-MLLT3 (often termed MLL-AF9)-driven AMLs have distinct transcriptional programmes, distinct cytosine methylation profiles, more rapid growth and a poorer response to therapy when they arise from haematopoietic stem cells as compared to more differentiated granulocyte-monocyte progenitors.…”

“…For example, RUNX1, DNMT3A and FLT3 mutations have been associated with inferior longterm survival (Ley et al, 2010;Schnittger et al, 2011;Patel et al, 2012), yet none of these mutations predicted induction failure in the study reported by Brown et al (2016). This suggests a disconnection between the mechanisms that cause induction failure (i.e.…”

“…A new study by Brown et al (2016) highlights both the potential value and the possible pitfalls of using genomic profiling to predict chemotherapy resistance in CN AML patients. The authors performed targeted DNA sequencing to identify mutations that predict induction failure and, by extension, chemotherapy resistance, in both adult and paediatric AML patients.…”

“…The paper by Brown et al (2016) lays out clear challenges for the future of genomics in AML treatment, particularly with regard to induction failure. Their findings suggest that somatic mutation profiles may need to be integrated with other modalities -including transcriptional, epigenetic and proteomic profiling -to arrive at a model that accurately predicts chemotherapy resistance.…”

“…Finally, SETBP1, ASXL1 and RELN mutations will need to be independently validated for their role in induction failure as they may guide treatment decisions for a subset of CN AML patients and may open new lines of investigation into the mechanisms that underlie chemotherapy resistance. These are navigable challenges, and the work by Brown et al (2016) provides an important step toward more personalized therapies for patients with CN AML.…”