Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates

Gu, Xiaorong; Ebrahem, Quteba; Mahfouz, R.; Hasipek, Metis; Enane, Francis; Radivoyevitch, Tomas; Rapin, Nicolas; Przychodzen, Bartlomiej; Hu, Zhenbo; Balusu, Ramesh; Cotta, Claudiu V.; Wald, David N.; Argueta, Christian; Landesman, Yosef; Martelli, Maria Paola; Falini, Brunangelo; Carraway, Hetty E.; Porse, Bo T.; Maciejewski, Jaroslaw P.; Jha, Babal K.; Saunthararajah, Yogen

doi:10.1172/jci97117

Cited by 103 publications

(122 citation statements)

References 98 publications

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“…When NPM1c is experimentally shifted from the cytoplasm, H3K27Ac is reduced, particularly at HOX loci, and inhibition of KMT2A‐menin and DOT1L, which target H3K4 and H3K79 methylation, also leads to reduced HOX expression . NPM1c may also dysregulate transcriptional networks by binding and shuttling PU.1 out of the nucleus; restoration of nuclear PU.1 switched RUNX1 and CEBPA interactomes from repressive to activating complexes, suggesting that NPM1c can lead to altered nuclear TF complexes …”

Section: Network Disruption Via Transcription Factorsmentioning

confidence: 99%

Transcriptional networks in acute myeloid leukemia

Thoms

Beck

Pimanda

2019

Genes Chromosomes & Cancer

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Acute myeloid leukemia (AML) is a complex disease characterized by a diverse range of recurrent molecular aberrations that occur in many different combinations. Components of transcriptional networks are a common target of these aberrations, leading to network‐wide changes and deployment of novel or developmentally inappropriate transcriptional programs. Genome‐wide techniques are beginning to reveal the full complexity of normal hematopoietic stem cell transcriptional networks and the extent to which they are deregulated in AML, and new understandings of the mechanisms by which AML cells maintain self‐renewal and block differentiation are starting to emerge. The hope is that increased understanding of the network architecture in AML will lead to identification of key oncogenic dependencies that are downstream of multiple network aberrations, and that this knowledge will be translated into new therapies that target these dependencies. Here, we review the current state of knowledge of network perturbation in AML with a focus on major mechanisms of transcription factor dysregulation, including mutation, translocation, and transcriptional dysregulation, and discuss how these perturbations propagate across transcriptional networks. We will also review emerging mechanisms of network disruption, and briefly discuss how increased knowledge of network disruption is already being used to develop new therapies.

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Section: Network Disruption Via Transcription Factorsmentioning

confidence: 99%

Transcriptional networks in acute myeloid leukemia

Thoms

Beck

Pimanda

2019

Genes Chromosomes & Cancer

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“…Efficacy reduction with dose reduction may not apply, however, to the nucleoside analogue decitabine, because it has a molecular‐targeted action of depleting DNA methyltransferase 1 (DNMT1) that occurs, and is saturated at, low decitabine concentrations (generally <1 μM). This molecular‐targeted action can cytoreduce p53‐null chemorefractory myeloid malignancies via terminal differentiation instead of apoptosis, simultaneously sparing normal haematopoiesis (Hu, et al , ; Hu et al , ; Ng et al , ; Negrotto et al , ; Tsai et al , ; Gu et al , ; Saunthararajah et al , ; Gu et al , ; Velcheti et al , ). Higher decitabine doses/concentrations (generally >1 μmol/l), by causing cytotoxicity, limit feasible exposure times for the S‐phase‐dependent DNMT1‐depleting effect, and can further compromise treatment goals by destroying normal haematopoietic cells.…”

Section: Pretreatment Characteristics Of Patients With Blood Count Chmentioning

confidence: 99%

“…Thus, a decitabine regimen designed and previously demonstrated to be non‐cytotoxic yet DNMT1‐depleting in non‐human primates and humans (Saunthararajah et al , ; Olivieri et al , ; Lavelle et al , ; Saunthararajah et al , ) produced durable responses (follow‐up was for up to 6·5 years) in myeloid malignancies across the clinico‐pathologic spectrum of disease — that is, in patients with MDS, MDS/MPN overlap, MPN or AML and in disease containing diverse genetic abnormalities — consistent with scientific data implicating DNMT1 as a mutation‐agnostic target that operates in a final common pathway of myeloid transformation (Hu et al , ; Hu et al , ; Ng et al , ; Negrotto et al , ; Gu et al , ; Saunthararajah et al , ; Gu et al , ; Velcheti et al , ). Likewise, a broad spectrum of activity has been observed with standard intravenously infused regimens of decitabine [reviewed in Saunthararajah ()].…”

Section: Pretreatment Characteristics Of Patients With Blood Count Chmentioning

confidence: 99%

“…Efficacy reduction with dose reduction may not apply, however, to the nucleoside analogue decitabine, because it has a molecular-targeted action of depleting DNA methyltransferase 1 (DNMT1) that occurs, and is saturated at, low decitabine concentrations (generally <1 lM). This molecular-targeted action can cytoreduce p53-null chemorefractory myeloid malignancies via terminal differentiation instead of apoptosis, simultaneously sparing normal haematopoiesis (Hu, et al, 2010;Hu et al, 2011;Ng et al, 2011;Negrotto et al, 2012;Tsai et al, 2012;Gu et al, 2014;Saunthararajah et al, 2015;Gu et al, 2018;Velcheti et al, 2018).…”

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confidence: 99%

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Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies

et al. 2019

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Summary The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular‐targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non‐cytotoxic DNMT1‐depletion can cytoreduce even p53‐null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off‐target anti‐metabolite effects/cytotoxicity, and then administered these well‐tolerated doses frequently 1–2X/week to increase S‐phase dependent DNMT1‐depletion, and used a Myeloid Malignancy Registry to evaluate long‐term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well‐tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.

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“…CEBPA is frequently altered in MDS/MPN and AML by loss-of-function (LOF) mutations or by (epi)genetic alterations that suppress CEBPA expression, together accounting for ~70% of molecular alterations in de novo AML ( Fig. 1A, (Cancer Genome Atlas Research et al, 2013;Ernst et al, 2010;Gu et al, 2018;Guo et al, 2012;Pabst et al, 2001a;Perrotti et al, 2002;Zheng et al, 2004)). Further, Cebpa LOF leads to a block in myeloid differentiation, contributing to AML-like diseases in mouse models (Bereshchenko et al, 2009;Kirstetter et al, 2008;Pabst et al, 2001b;Porse et al, 2005;Zhang et al, 1997;Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chronic Interleukin-1 exposure triggers selective expansion ofCebpa-deficient multipotent hematopoietic progenitors

Higa

2020

Preprint

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The early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1β (IL-1β), impacts Cebpadeficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found that Cebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection for Cebpa loss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1β, and competitively expand. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.

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Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates

Abstract: Conflict of interest:CA and YL have ownership in KaryoPharm and YS has ownership in EpiDestiny. CA and YL receive income from KaryoPharm. YS hold patents involving tetrahydrouridine, decitabine, and 5-azacytidine (US patents 9,259,469 B2;9,265,785 B2;9,895,391 B2).

Cited by 103 publications

References 98 publications

Transcriptional networks in acute myeloid leukemia

Transcriptional networks in acute myeloid leukemia

Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies

Chronic Interleukin-1 exposure triggers selective expansion ofCebpa-deficient multipotent hematopoietic progenitors

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