Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Liang, Kaiwei; Volk, Andrew; Haug, Jeffrey S.; Marshall, Stacy A.; Woodfin, Ashley R.; Bartom, Elizabeth T.; Gilmore, Joshua M.; Florens, Laurence; Washburn, Michael P.; Sullivan, Kelly D.; Espinosa, Joaquín M.; Cannova, Joseph; Zhang, Jiwang; Smith, Edwin R.; Crispino, John D.; Shilatifard, Ali

doi:10.1016/j.cell.2016.12.011

Cited by 99 publications

(125 citation statements)

References 51 publications

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“…As this study illustrates, the impact of fusion transcripts in AML is both broad and age dependent. Recognition and comprehensive testing for these alterations are key first steps in the development of new modes of targeted therapy 33 .…”

Section: Discussionmentioning

confidence: 99%

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Bolouri

Farrar

Triche

et al. 2017

Nat Med

629

681

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We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children’s Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger–encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

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Section: Discussionmentioning

confidence: 99%

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Bolouri

Farrar

Triche

et al. 2017

Nat Med

629

681

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“…As this study comprehensively illustrates, the impact of fusion transcripts is both broad and age-dependent in pediatric AML. Recognition and comprehensive testing for these alterations are key first steps in the development of new and potentially novel modes of targeted therapy 30 .…”

Section: Discussionmentioning

confidence: 99%

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Bolouri

Triche

Ries

et al. 2017

Preprint

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However, the relevance of these findings to childhood AML remains unclear, since several of the most 53 common adult mutations appear far less prevalent in pediatric AML 6,7 . 54To date, no comprehensive characterization of pediatric AML has been described. Here, we report the 55 initial results of the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) 56 AML initiative, a collaborative COG/NCI project to comprehensively characterize the mutational, 57 transcriptional, and epigenetic landscapes of a large, well-annotated cohort of pediatric AML. 58Comparing AML molecular profiles across age groups, we show that stark differences in mutations,d 59 structural variants and DNA methylation distinguish AML in infants, children, adolescents, and adults. 60 Results 61 Overview of cohort characteristics 62A total of 1023 children enrolled in COG studies are included in the TARGET AML dataset. 63Comprehensive clinical data, including clinical outcomes and test results for common sequence 64 aberrations (outlined in We carried out analyses of microRNA, mRNA, and/or DNA methylation in 412 subjects. A summary of 94 the assays performed and case-assay overlap is presented in Fig. S3. We compared our verified variants 95 to those of 177 adult AML cases from The Cancer Genome Atlas (TCGA) project 3 , stratified by the age 96 groupings outlined in Fig. 1a. The TARGET and TCGA discovery cohorts both contained numerous AYA 97 patients (Table S3). Importantly, our conclusions regarding the molecular characteristics of this age 98 group are identical when analyzing either or both cohorts (Fig. S4). 99 Somatic gene mutations in pediatric AML 100Like adult AML, pediatric AML has one of the lowest rates of mutation among molecularly well-101 characterized cancers (Fig. S5), with < 1 somatic, protein-coding change per megabase in most cases. 102However, the landscape of somatic variants in pediatric AML is markedly different from that reported in 103 adults 3,4 (Figs. 2b, S6-S7, Table S4). RAS, KIT, and FLT3 alterations, including novel, pediatric-specific 104 FLT3 mutations (FLT3.N), are more common in children. Mutational burden increases with age, yet older 105 patients have relatively fewer recurrent cytogenetic alterations. Indeed, the number of coding SNVs, 106 within and across cohorts, is best predicted by age (Fig. 2c, p<10 -15 ) and by cytogenetic subgroup. In 107 contradistinction to the higher prevalence of small sequence variants in older patients, recurrent 108 structural alterations, fusions, and focal copy number aberrations are more common in younger patients 109 (Figs. 2d-e, p<10 -3 , see below). Patients with CBFA2T3-GLIS2, KMT2A, or NUP98 fusions tend to have 110 . CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/125609 doi: bioRxiv preprint first posted online Jun. 13, 2017; fewer mutations (p<10 -9 ), with subgroups demonstrating inferior clinical outcome...

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“…Of interest, a recent study described a unique mechanism for the treatment of MLL-r leukemia via IRAK inhibitors that prevented the degradation of wild-type MLL protein by interfering with the function of UBE2O, thereby inhibiting the proliferation of MLL leukemia cells. 38 Accordingly, we hypothesize that the truncated MLL* protein also exerts such complementary functions.…”

Section: Discussionmentioning

confidence: 99%

Relatively favorable prognosis for MLL‐rearranged childhood acute leukemia with reciprocal translocations

Liu

Ding

Liang

et al. 2018

Pediatric Blood & Cancer

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Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Cited by 99 publications

References 51 publications

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Relatively favorable prognosis for MLL‐rearranged childhood acute leukemia with reciprocal translocations

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