RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

Carr, Ryan M.; Vorobyev, Denis; Lasho, Terra L.; Marks, David L.; Tolosa, Ezequiel J.; Vedder, Alexis; Almada, Luciana L.; Yurcheko, Andrey; Padioleau, Ismaël; Alver, Bonnie; Coltro, Giacomo; Binder, Moritz; Safgren, Stephanie L.; Horn, Isaac P.; You, Xiaona; Solary, Éric; Balasis, Maria E.; Berger, Kurt; Hiebert, James W; Witzig, Thomas E.; Buradkar, Ajinkya; Graf, Temeida; Valent, Peter; Mangaonkar, Abhishek A.; Robertson, Keith D.; Howard, Matthew T.; Kaufmann, Scott H.; Pin, Christopher L.; Fernández-Zapico, Martín E.; Geißler, Klaus; Droin, Nathalie; Padron, Eric; Zhang, Jing; Nikolaev, Sergey I.; Patnaik, Mrinal M.

doi:10.1038/s41467-021-23186-w

Cited by 52 publications

(79 citation statements)

References 68 publications

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“…Recently, genetic differences were assessed between subtypes in 973 molecularly annotated Mayo Clinic-GFM-Austrian CMML patients. In this analysis NRAS mutations alone did not reach statistical significance as an independent factor impacting AML-free survival, however, the combined oncogenic RAS-pathway category including NRAS, KRAS and CBL was statistically significant in a model that only included genetic factors (74). Considering the fact, that spontaneous colony formation in CMML functionally covers the most frequent RASopathy gene mutations (38) these data are in line with findings in a small study which have been previously reported.…”

Section: Progression Of Cmml and Transformation To Amlsupporting

confidence: 89%

“…In MP-CMML RAS-pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases including polo-like kinase 1 ( PLK1) ( 74 ) as shown in a study using a multiomics platform and biochemical and molecular analyses. In this study unmutated MLL regulated PLK1 transcript levels via promoter monomethylation of lysine 4 of histone 3.…”

Section: Treatment Of Cmmlmentioning

confidence: 99%

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Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches

Geißler

2021

Front. Oncol.

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Numerous examples in oncology have shown that better understanding the pathophysiology of a malignancy may be followed by the development of targeted treatment concepts with higher efficacy and lower toxicity as compared to unspecific treatment. The pathophysiology of chronic myelomonocytic leukemia (CMML) is heterogenous and complex but applying different research technologies have yielded a better and more comprehensive understanding of this disease. At the moment treatment for CMML is largely restricted to the unspecific use of cytotoxic drugs and hypomethylating agents (HMA). Numerous potential molecular targets have been recently detected by preclinical research which may ultimately lead to treatment concepts that will provide meaningful benefits for certain subgroups of patients.

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Section: Progression Of Cmml and Transformation To Amlsupporting

confidence: 89%

Section: Treatment Of Cmmlmentioning

confidence: 99%

Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches

Geißler

2021

Front. Oncol.

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“…The mutations that activated RAS family members drove the MP variants of CMML, while the EZH2 , IDH1/2 , NPM1 , and FLT3 -ITD mutations were correlated with acute leukemia transformation. Altogether, this study demonstrates a key role of RAS pathway mutations, particularly NRAS , in the clonal evolution from CMML (at diagnosis) to sAML [ 48 ].…”

Section: Pathogenesis and Cmml Treatmentmentioning

confidence: 88%

“…It is worth considering the large-scale study conducted by Carr and colleagues [ 48 ]. According to whole-exome sequencing data, CMML-associated driver mutations were divided into three groups: (1) primary drivers of chronic CMML and the late transformation stage; (2) mutations of the late transformation phase; and (3) molecular abnormalities that were detected in the chronic CMML phase, but were absent during the late transformation phase.…”

Section: Pathogenesis and Cmml Treatmentmentioning

confidence: 99%

Mouse Models of CMML

Belotserkovskaya

Demidov

2021

IJMS

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Chronic myelomonocytic leukemia (CMML) is a rare and challenging type of myeloproliferative neoplasm. Poor prognosis and high mortality, associated predominantly with progression to secondary acute myeloid leukemia (sAML), is still an unsolved problem. Despite a growing body of knowledge about the molecular repertoire of this disease, at present, the prognostic significance of CMML-associated mutations is controversial. The absence of available CMML cell lines and the small number of patients with CMML make pre-clinical testing and clinical trials complicated. Currently, specific therapy for CMML has not been approved; most of the currently available therapeutic approaches are based on myelodysplastic syndrome (MDS) and other myeloproliferative neoplasm (MNP) studies. In this regard, the development of the robust CMML animal models is currently the focus of interest. This review describes important studies concerning animal models of CMML, examples of methodological approaches, and the obtained hematologic phenotypes.

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“…RAS-signalling mutations skew haematopoiesis to the myelomonocytic lineage and promote increased proliferation. In CMML, the presence of oncogenic RAS pathway genes has been associated with a more aggressive subtype and leukaemic transformation towards AML [177]. There are other pathway genes involved in leukaemia such as PTPN11 which is mutated in 4% of AML patients [57].…”

Section: Mutations In Ras Membersmentioning

confidence: 99%

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Castro

Cadefau

2021

Cancers

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Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.

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RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

Cited by 52 publications

References 68 publications

Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches

Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches

Mouse Models of CMML

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

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