Format

Send to

Choose Destination
BMC Cancer. 2015 Sep 7;15:621. doi: 10.1186/s12885-015-1639-5.

A novel somatic mutation in ACD induces telomere lengthening and apoptosis resistance in leukemia cells.

Author information

1
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. jf.spinella@gmail.com.
2
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. cassart.pauline@gmail.com.
3
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. nicolasgarnier3000@gmail.com.
4
Lady Davis Institute Jewish General Hospital, Montreal, Qc, Canada. pmp.rousseau@gmail.com.
5
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. claire.drullion@gmail.com.
6
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. cricher.hsj@gmail.com.
7
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. manon.ouimet@recherche-ste-justine.qc.ca.
8
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. vr.saillour@gmail.com.
9
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. jasmine.healy@umontreal.ca.
10
Lady Davis Institute Jewish General Hospital, Montreal, Qc, Canada. chantal.autexier@mcgill.ca.
11
Departments of Anatomy, Cell Biology and Medicine, McGill University, Montreal, Qc, Canada. chantal.autexier@mcgill.ca.
12
Division of Hematology-Oncology, Sainte-Justine UHC Research Center, 3175 Côte Ste-Catherine, H3T 1C5, Montréal, Québec, Canada. daniel.sinnett@umontreal.ca.
13
Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Qc, Canada. daniel.sinnett@umontreal.ca.

Abstract

BACKGROUND:

The identification of oncogenic driver mutations has largely relied on the assumption that genes that exhibit more mutations than expected by chance are more likely to play an active role in tumorigenesis. Major cancer sequencing initiatives have therefore focused on recurrent mutations that are more likely to be drivers. However, in specific genetic contexts, low frequency mutations may also be capable of participating in oncogenic processes. Reliable strategies for identifying these rare or even patient-specific (private) mutations are needed in order to elucidate more personalized approaches to cancer diagnosis and treatment.

METHODS:

Here we performed whole-exome sequencing on three cases of childhood pre-B acute lymphoblastic leukemia (cALL), representing three cytogenetically-defined subgroups (high hyperdiploid, t(12;21) translocation, and cytogenetically normal). We applied a data reduction strategy to identify both common and rare/private somatic events with high functional potential. Top-ranked candidate mutations were subsequently validated at high sequencing depth on an independent platform and in vitro expression assays were performed to evaluate the impact of identified mutations on cell growth and survival.

RESULTS:

We identified 6 putatively damaging non-synonymous somatic mutations among the three cALL patients. Three of these mutations were well-characterized common cALL mutations involved in constitutive activation of the mitogen-activated protein kinase pathway (FLT3 p.D835Y, NRAS p.G13D, BRAF p.G466A). The remaining three patient-specific mutations (ACD p.G223V, DOT1L p.V114F, HCFC1 p.Y103H) were novel mutations previously undescribed in public cancer databases. Cytotoxicity assays demonstrated a protective effect of the ACD p.G223V mutation against apoptosis in leukemia cells. ACD plays a key role in protecting telomeres and recruiting telomerase. Using a telomere restriction fragment assay, we also showed that this novel mutation in ACD leads to increased telomere length in leukemia cells.

CONCLUSION:

This study identified ACD as a novel gene involved in cALL and points to a functional role for ACD in enhancing leukemia cell survival. These results highlight the importance of rare/private somatic mutations in understanding cALL etiology, even within well-characterized molecular subgroups.

PMID:
26345285
PMCID:
PMC4562123
DOI:
10.1186/s12885-015-1639-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center