The genetic basis of early T-cell precursor acute lymphoblastic leukaemia
James R. Downing ,Charles G. Mullighan
Nature 2012 | Vol 481 | 157-163
Presenter : Chih-Hao, Wu
Commentator: Dr. H. Sunny Sun
Date/Time: 2012/05/24, 16:10~17:00
Location: Room 602, Med College Building
Background:
Acute lymphoblastic leukaemia (ALL) is the most common malignant leukemia of childhood,
especially among 2-3 years. ALL is a spectrum of disease comprised of different cell types, most of
the cases are B cell lineage (85%), and 15% are T-cell lineage. Recent studies have identified a new
subtype of T-cell ALL which shows stem-cell-like features and is termed early T-cell precursor (ETP)
ALL . The early T-cell precursor acute lymphoblastic leukemia (ETP ALL) that comprises up to 15% of
T-ALL and has a poor prognosis when treated with lymphoid cell-directed chemotherapy. Several
cell surface markers have been characterized in ETP ALL. A lack of expression of the T-cell surface
markers CD1a and CD8 and aberrant expression of myeloid and haematopoietic stem cell markers
have been observed. Nevertheless the genetic basis of ETP ALL is still unknown.
Objective/Hypothesis:
The authors wants to identify new genetic targets of recurrent mutation in ETP ALL.
Results:
By using whole genome sequencing (WGS) and “clipping reveals structure” (CREST) algorithm to
assess the frequency of the somatic mutations in 94 T-cell acute lymphoblastic leukemia cases (52
ETP and 42 non-ETP), the authors identified an average of 1140 sequence mutations and 12
structural variations per case. 51% of the structural variations had breakpoints in the genes which
have a role in haemotopoiesis and leukaemogenesis. Most of these structural variations were
predicted to result in loss-of-function or complex translocation. In addition, WGS results showed a
high frequency of mutations in genes regulating cytokine receptor and Ras signaling, and in genes
involving in the haematopoietic and lymphoid development, and histone modification.
Conclusion:
Mutation of genes regulating cytokine receptor, Ras signalling and epigenetic modification is a
common feature of acute myeloid leukemia but not common in ALL. This observation gives a new
possibility of treatment strategy in ETP ALL.