SUMMARY Somatic loss-of-function mutations in the ten-eleven-translocation-2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in the hematopoietic compartment have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment which leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2+/− mice also displayed increased stem cell self-renewal and extramedulary hematopoiesis, suggesting Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.
Summary Recurrent somatic ASXL1 mutations occur in patients with myelodysplasia (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML), and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here we identify that ASXL1 mutations result in loss of PRC2-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data we identify targets of ASXL1 repression including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the Polycomb repressive complex 2 (PRC2), and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.
Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML. (1). Mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF (2-6), underscoring the importance of activated JAK-STAT signaling to the pathogenesis of chronicphase MPN. Despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). Leukemic transformation occurs in 1%, 4%, and 20% of patients over a 10-y period in ET, PV, and PMF, respectively (7). MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo (8). Advanced age (>60 y) and exposure to chemotherapy increase the risk of leukemic transformation; however, the mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. Importantly, the use of standard AML therapies, including induction chemotherapy, has not been shown to improve outcome for patients with post-MPN AML (8, 9). These data indicate a need for new models and improved therapeutic approaches to improve outcomes for patients who have transformed from MPN to AML and to identify genetic lesions associated with leukemic transformation.Genetic studies of paired samples before and after leukemic transformation have suggested there are at least two distinct routes for leukemic transformation. Some patients who present with a JAK2/MPL-positive MPN progress to JAK2/MPL-positive AML that is associated with the acquisition of additional genetic alterations (10-13). A second, more complex route to AML from MPN has been described in which a JAK2/MPL-positive MPN is followed by JAK2/MPL-negative AML (14, 15). Clonality studies using X-chromosome inactivation in informative females demonstrated that JAK2/MPL-positive MPN and JAK2/MPL-negative AML are clonally related, consistent with transformation of an antecedent, preJAK2...
Summary Specific combinations of Acute Myeloid Leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2−/−;Flt3ITD progenitors (LSK CD48+CD150−) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3ITD mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.
Loss of Asxl1 results in myelodysplastic syndrome, whereas concomitant deletion of Tet2 restores HSC self-renewal and triggers a more severe disease phenotype distinct from that seen in single-gene knockout mice.
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