Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy1,2, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene3 and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase)4. Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (, and ) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS. We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. .

Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.