RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance

High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder

“…Two additional somatic alterations were identified in this patient at AML stage: a K-RAS mutation and a t(1;3)(p36; q26) inducing a PRDM16 overexpression. Recently, RocheLestienne et al 23 confirmed that PRDM16 is an important partner of RUNX1 in the progression of chronic myeloid leukemia to AL. 23 Furthermore, an association, possibly indicating cooperation, has been observed between point mutations of RUNX1 and RAS, especially in therapy-related AML.…”

“…Recently, RocheLestienne et al 23 confirmed that PRDM16 is an important partner of RUNX1 in the progression of chronic myeloid leukemia to AL. 23 Furthermore, an association, possibly indicating cooperation, has been observed between point mutations of RUNX1 and RAS, especially in therapy-related AML. 24 In this study, 4 patients with AL underwent allogeneic bone marrow transplantation (ABMT) from an HLA-matched related donor.…”

Chronic myeloid leukemia: mechanisms of blastic transformation

“…The genetic lesions observed in CML-BP patients in the past and now since the introduction of TKIs mostly include the presence of additional chromosomes, gene deletions, gene insertions, and/or point mutations (including BCR-ABL1 mutations) (20)(21)(22), but patterns differ in myeloblastic and lymphoblastic transformations (23). At the molecular level, the most common mutations detectable (other than those in the BCR-ABL1 kinase domain) occur at the loci of the tumor suppressor genes P53 (20%-30% of cases) and the runt-related transcription factor gene (RUNX1) (38% of cases) in myeloid BP and at the loci of cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/B) (50% of cases) and Ikaros transcription factor (IKZF1) (55% of cases) in lymphoid BP (22,(24)(25)(26)(27)(28).…”

Prdm16 is a physiologic regulator of hematopoietic stem cells

“…PR domain-containing 16 (PRDM16), a 140-kDa zinc finger protein, was originally discovered as a fusion partner in t(1:3)(p36;q21) translocations in acute myeloblastic leukemia (AML) 10,11 and later in t(1;21)(p36;q22) translocations fused to RUNX1. 12,13 In addition, elevated PRDM16 expression, because of promoter hypomethylation, is frequently observed in karyotypically normal AML. 14 Deletion of the PR domain, which shows homology with a SET chromatin remodeling domain and is also present in EVI1, 10 appears important for the leukemogenic properties of human PRDM16.…”

“…14 Deletion of the PR domain, which shows homology with a SET chromatin remodeling domain and is also present in EVI1, 10 appears important for the leukemogenic properties of human PRDM16. Translocations involving PRDM16 invariably delete the PR domain, [10][11][12][13] whereas PR-deleted Prdm16 causes AML in p53 Ϫ/Ϫ mice. 14 Furthermore, both Prdm16 and Evi1 are frequent targets of insertional mutagenesis in mice, causing deletion of the PR domain.…”