Activating Notch1 mutations in mouse models of T-ALL

Abstract

Recent studies have demonstrated that most patients with T-cell acute lymphocytic leukemia (T-ALL) have activating mutations in NOTCH1. We sought to determine whether these mutations are also acquired in mouse models of T-ALL. We sequenced the heterodimerization domain and the PEST domain of Notch1 in our mouse model of TAL1-induced leukemia and found that 74% of the tumors harbor activating mutations in Notch1. Cell lines derived from these tumors undergo G 0 /G 1 arrest and apoptosis when treated with a ␥-secretase inhibitor. In addition, we found activating Notch1 mutations in 31% of thymic lymphomas that occur in mice deficient for various combinations of the H2AX, Tp53, and Rag2

Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

“…A cooperative role between Ikaros and Notch mutations and pre-TCR signalling in T cell transformation and leukemia has been highlighted [6,8,10]. Consistent with these results T-ALL is greatly suppressed in Rag1-deficient Ikzf1 Plstc/+ mice where the TCR-␤ chain cannot be rearranged to assemble pre-TCR (unpublished data).…”

“…This translocation is present in <1% of human T-ALL but several studies have provided evidence that Notch signalling in T cell leukemias and lymphomas is often elevated even in the absence of genomic rearrangements [4,5]. Somatic mutations that alter the NOTCH1 protein-coding sequence have been found in more than 50% of human T-ALL with diverse molecular subtypes [6]. These were found largely in the extracellular heterodimerization (HD) domain, and truncating or missense mutations in the C-terminal PEST domain that increase stability of ICN [6][7][8][9][10].…”

“…Somatic mutations that alter the NOTCH1 protein-coding sequence have been found in more than 50% of human T-ALL with diverse molecular subtypes [6]. These were found largely in the extracellular heterodimerization (HD) domain, and truncating or missense mutations in the C-terminal PEST domain that increase stability of ICN [6][7][8][9][10]. The extent to which these individual NOTCH1 mutations in T-ALL confer a growth advantage or malignant transformation is unclear.…”

“…FBXW7 [20,21] and Ikaros [22][23][24]) have been identified. Mice with germline mutations that inactivate the transcriptional regulator Ikaros (gene symbol Ikzf1) develop T-ALL exclusively [23,25] and the resulting malignancies often have activating NOTCH1 mutations [6,23,24]. Ikzf1 somatic mutations are also frequently found in combination with NOTCH1 mutations in mouse retrovirus-promoted T-ALL [18] and in human B-ALL and T-ALL [26,27].…”

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

“…[18][19][20][21][22][23] They suggest that the initiating event occurs in T cells in the thymus or in the bone marrow. The transformed cells then readily spread to other organs and the PB, and a highly malignant T-cell leukemia evolves rapidly.…”