We posted the original manuscript “Therapeutic remodeling of CBP transcription factor complex controls oncogenic gene expression in acute myeloid leukemia” as a bioRxiv preprint during the pause in research activities caused by the COVID-19 surge in New York City in spring of 2020.

By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB in AML cells, we found that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. We proposed that convergently organized transcription factor complexes in AML cells control oncogenic gene expression programs. We still needed to prove experimentally that this model explained aberrant gene expression in diverse forms of AML.

So while we continued work, we tried a new form of scientific publishing, by submitting the preprint for peer review via Review Commons. The reviewers suggested many experiments, all of which either served to prove the proposed mechanism or clarify its presentation. You can read the Review Commons reviews of the original manuscript and our responses at bioRxiv.

This “publish, then review” model of publishing was recently endorsed at eLife, which will use it as its standard process starting this year.

With additional experiments, we have now found that the oncogenic functions of MYB are mediated by its aberrant assembly with LYL1, E2A, C/EBP, LMO2 and SATB1 factors. They are organized convergently in diverse AML subtypes, and in part associated with their inappropriate co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and redistribution of CBP/P300 with alternative factors such as RUNX1 to induce differentiation and apoptosis. Aberrant assembly and sequestration of MYB:CBP/P300 provide a unifying mechanism of oncogenic gene expression. This defines a strategy for their pharmacologic reprogramming and targeting for leukemias and other cancers caused by dysregulated gene control. Read the published paper at eLife, with all data openly available at Zenodo, and explanation at MSKCC News.

We anticipate that future development of clinical-grade MYB inhibitors will make it possible to test this new therapeutic strategy in clinical trials for patients with blood cancers and many other MYB-dependent malignancies. And we hope that new forms of scientific publishing will make science more rigorous, more inclusive, and more enjoyable.

The post A new year for new science and a new science publishing model: Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia appeared first on Kentsis Research Group at Memorial Sloan Kettering Cancer Center.

This new article integrates recently discovered mechanisms of developmental mutations, with new and established findings of inherited cancer predisposition and oncogenic pathogens. By relating the findings of recent human genomic studies with the fundamental mechanisms of cancer pathogenesis, this article also explains key concepts for the clinical diagnosis and rational therapy of patients, as part of recent molecular and precision oncology paradigms. Lastly, a discussion of emerging technologies and therapies provides compelling directions for future work to define the basic molecular and genetic mechanisms of early onset cancers, and improved strategies for their treatment, screening and potential prevention.

While inheritance of germ-line mutations in genes causing cancer predisposition syndromes, or exposure to environmental mutagens and oncogenic pathogens is responsible for early onset of cancer, only approximately 10% of individuals are estimated to have such cancer predisposition. This raises the question of what causes early onset cancers in the majority of children and young adults. With Steven Frank, we advance the developmental mutator hypothesis to explain early onset cancer development.

This idea is based on the recently published findings of distinct features of oncogenic mutations observed in childhood and young adult cancers, and their expression of endogenous mutagenic DNA enzymes. This involves the majority of blood and solid tumors affecting children and young adults, including leukemias, medulloblastomas, neuroblastomas, and sarcomas. The developmental mutator model explains recent findings of widespread somatic genetic mosaicism in normal human tissues, and predicts developmental DNA rearrangements in specific tissues which give rise to early onset cancers in children and young adults without inherited cancer predisposition.

Many questions remain, including what controls the activity of developmental mutators? What processes cause developmental mutations in developing sarcomas, kidney tumors, leukemias, and brain tumors that lack PGBD5 and RAG1/2? How do interactions among developmental mutators, their physiologic control processes and exposures, and familial inheritance converge in human development and disease?

We are always looking for colleagues, collaborators, and students to make progress in these questions.

The post Why do young people get cancer? Developmental mutators, mutagens, and inheritance. appeared first on Kentsis Research Group at Memorial Sloan Kettering Cancer Center.

In a long-term collaboration with the Children’s Oncology Group, Hanno Steen, Elizabeth Mullen and many colleagues, and led by Michael Ortiz, we now describe a new approach for the discovery of urine biomarkers for kidney tumors, including Wilms tumor, the most common childhood kidney tumor. Using urine proteomics, we now provide a comprehensive profile of urinary biomarkers for most of kidney tumors, including Wilms tumors, renal rhabdoid tumors, kidney clear cell sarcomas, and renal cell carcinomas. In particular, we found new markers associated with Wilms tumor relapse, and confirmed the prognostic significance of urine prohibitin in multiple independent patient cohorts. Using functional genetic experiments, we found that overexpression of prohibitin is both necessary and sufficient to confer resistance to diverse chemotherapy drugs. This involved an unanticipated mechanism of aberrant apoptotic cytochrome c release through dysregulation of mitochondrial cristae structure, providing an explanation for the abnormal mitochondrial morphology first noted in Wilms tumors more than 50 years ago.

These findings define urine prohibitin as a potential clinical biomarker to improve therapy stratification and enable non-invasive monitoring of response and early disease relapse. In addition, our study reveals a general mechanism of chemotherapy resistance that is expected to have broad significance, given the prevalence of prohibitin overexpression across many cancer types.

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Now, convergent research from our group and Chris Vakoc indicates that seemingly general transcriptional co-activators can have extraordinarily selective functions in cancer cells, and in the case of AML, in their cooperation with the transcription factor MYB, as summarized in this Twitter thread.

In particular, we have now engineered a prototypical stabilized and cell penetrant peptidomimetic MYB inhibitor, termed MYBMIM, and defined its mechanism and activity against AML. MYBMIM and its inactive analogue TG3 provide a tool for studying MYB-dependent gene control and transcriptional co-activation. In turn, their improved derivatives are expected to offer new therapeutic agents for therapeutic blockade of oncogenic gene expression.

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