Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia

M Kontro, H Kuusanmäki, S Eldfors, T Burmeister… - Leukemia, 2014 - nature.com
M Kontro, H Kuusanmäki, S Eldfors, T Burmeister, EI Andersson, Ø Bruserud…
Leukemia, 2014nature.com
STAT5 has an important role in many hematologic malignancies, but constitutive activation
is often a secondary event. 1 Mutations to STAT5B and their functional significance were
recently discovered in large granular lymphocytic (LGL) leukemia. 2 The mutations located
in the SRC homology 2 (SH2) domain of STAT5B lead to constitutive phosphorylation of the
mutant protein, increased transcriptional activity and activation of downstream target genes.
However, activating mutations in STAT5B have thus far not been described in other cancers …
STAT5 has an important role in many hematologic malignancies, but constitutive activation is often a secondary event. 1 Mutations to STAT5B and their functional significance were recently discovered in large granular lymphocytic (LGL) leukemia. 2 The mutations located in the SRC homology 2 (SH2) domain of STAT5B lead to constitutive phosphorylation of the mutant protein, increased transcriptional activity and activation of downstream target genes. However, activating mutations in STAT5B have thus far not been described in other cancers. In T-cell acute lymphoblastic leukemia (T-ALL), a complex cooperation of multiple oncogenic aberrations leads to the development of the disease. 3 Approximately 9% of childhood T-ALL patients display IL7R gain-of-function mutations leading to constitutive activation of downstream targets. 4 The two main pathways induced by IL7R are PI3K/AKT/MTOR and JAK/STAT5. 5 In addition to mutations in IL7R, somatic JAK1 and JAK3 gain-offunction mutations are relatively prevalent in T-ALL presenting in 10.4% and 7% of adult patients, respectively. 6, 7 Activating mutations to IL7R, JAK1, JAK2 or JAK3 are estimated to occur in 20–30% of all T-ALL patients. 8 In naive T cells the stimulation of either JAK–STAT5 or PI3K pathway results in the induction of key anti-apoptotic factors, including B-cell lymphoma 2 (BCL-2) and myeloid cell leukemia sequence 1 (MCL1), while pro-apoptotic BCL-2 family members are inhibited. 9 In T-ALL, however, the STAT5 target genes are inadequately known. Here we report the identification of activating mutations to STAT5B in T-ALL accompanied by overexpression of BCL-XL (BCL2L1) and sensitivity to pan-BCL-2 inhibitors.
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