Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia

Wang, Lu; Birch, Noah W.; Zhao, Zibo; Nestler, Carson Meredith; Kazmer, Alexander; Shilati, Anthony; Blake, Alisha; Ozark, Patrick A.; Rendleman, Emily J.; Zha, Didi; Ryan, Caila; Morgan, Marc A.; Shilatifard, Ali

doi:10.1038/s43018-021-00199-4

Cited by 54 publications

(46 citation statements)

References 39 publications

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“…They are almost universally located at the C-terminal and give rise to prematurely truncated variants of ASXL1 that retain the N-terminal region, which suggests that the amino terminal domain of ASXL1 retains a functional activity important for tumorigenesis. 35,36 Also, the ASXL1 variant detected in our patient has similar functional properties, as was documented by Leon et al Briefly, the novel aberrant transcript is not mediated by nonsense-mediated decay (NMD) process; therefore, the transcript is not spliced correctly. Affecting the canonical acceptor splice site at intron 12, the variant results in full retention of intron 12 and truncated protein lacking C-terminus.…”

Section: Discussionsupporting

confidence: 82%

“…The majority of ASXL1 gene structure aberrations (66%; 47.2% frameshift and 18.8% nonsense mutations) detected in human cancers are predicted to encode premature stop codons. They are almost universally located at the C‐terminal and give rise to prematurely truncated variants of ASXL1 that retain the N‐terminal region, which suggests that the amino terminal domain of ASXL1 retains a functional activity important for tumorigenesis 35,36 . Also, the ASXL1 variant detected in our patient has similar functional properties, as was documented by Leon et al Briefly, the novel aberrant transcript is not mediated by nonsense‐mediated decay (NMD) process; therefore, the transcript is not spliced correctly.…”

Section: Discussionsupporting

confidence: 75%

“…It allowed to introduce molecularly targeted therapy, especially in pts with high molecular risk and a progressive disease. It is especially evident in the light of the recently published data concerning a possible targeted therapeutic approach for ASXL1 ‐mutated leukemia through the inhibition of ASXL1‐BAP1 catalytic activity 35 . The above‐mentioned strategy may delay the disease evolution to fibrotic phase, which itself is now considered an independent risk factor for a rapid blast progression of MPN 41,42 …”

Section: Discussionmentioning

confidence: 99%

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Rapid progression of myelofibrosis in polycythemia vera patient carrying SRSF2 c.284C>A p.(Pro95His) and unique ASXL1 splice site c.1720‐2A>G variant

Kanduła

Kroll-Balcerzak

Lewandowski

2022

Clinical Laboratory Analysis

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Background The prognosis in polycythemia vera (PV) is comparatively favorable, but individual myelofibrosis/leukemic progression risk is heterogeneous. About a quarter of patients progress to the fibrotic phase after 20 years. Methods Multiplex PCR, allele‐specific qPCR, high‐resolution melt analysis, and Sanger sequencing were used to detect BCR‐ABL, JAK2, ASXL1, SRSF2, U2AF1, and IDH1/2 variants. Results Herein, we present a PV patient with rapid progression to secondary myelofibrosis probably due to the coexistence of homozygous JAK2 V617F mutation, SRSF2 c.284C>A p.(Pro95His) and splice site variant of ASXL1 c.1720‐2A>G. The detected ASXL1 variant was first described in Bohring–Opitz syndrome and has not been reported in hematological malignancies so far. In the presented case, the ASXL1 VAF was stable (50%) during the 4‐year follow‐up, despite an evident increase in the JAK2 V617F VAF. Family history revealed cerebral palsy in the patient's grandson; however, germline character of the ASXL1 variant was excluded. Conclusion The biological consequences of the variant acquisition by hematopoietic stem cells (HSC) seem to be similar to other mutations of ASXL1 responsible for the truncation of ASXL1 protein, formation of hyperactive ASXL1–BAP1 (BRCA1‐associated protein‐1) complexes, and finally, the promotion of aberrant myeloid differentiation of HSC. Our report supports the hypothesis that ASXL1 alteration cooperates with JAK2 V617F leading to biased lineage skewing, favoring erythroid and megakaryocytic differentiation, accelerating the progression of PV to the fibrotic phase.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Rapid progression of myelofibrosis in polycythemia vera patient carrying SRSF2 c.284C>A p.(Pro95His) and unique ASXL1 splice site c.1720‐2A>G variant

Kanduła

Kroll-Balcerzak

Lewandowski

2022

Clinical Laboratory Analysis

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“…While there has been considerable debate on the mechanistic effects of leukemia-associated ASXL1 mutations, several recent studies ( Balasubramani et al 2015 ; Asada et al 2018 ; Wang et al 2021 ) have identified that the most common ASXL1 mutations generate a stable truncated protein that promotes the activity of the histone H2A lysine 119 deubiquitinase BAP1 ( Fig. 2 ).…”

Section: Novel Molecularly Targeted Therapies In Amlmentioning

confidence: 99%

“…2 ). These observations motivated Wang et al (2021) to screen for BAP1 catalytic inhibitors. A first-in-class BAP1 inhibitor abrogated truncated ASXL1 gene expression and tumor growth in vivo.…”

Section: Novel Molecularly Targeted Therapies In Amlmentioning

confidence: 99%

Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic

Bewersdorf

Abdel‐Wahab

2022

Genes Dev.

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Despite FDA approval of nine new drugs for patients with acute myeloid leukemia (AML) in the United States over the last 4 years, AML remains a major area of unmet medical need among hematologic malignancies. In this review, we discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations. In addition, we review progress in immune targeting of AML through anti-CD47, anti-SIRPα, and anti-TIM-3 antibodies; bispecific and trispecific antibodies; and new cellular therapies in development for AML.

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A guide to epigenetics in leukaemia stem cells

Agrawal‐Singh,

Bagri,

Sakakini

et al. 2023

Molecular Oncology

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Leukaemia stem cells (LSCs) are the critical seed for the growth of haematological malignancies, driving the clonal expansion that enables disease initiation, relapse and often resistance. Specifically, they display inherent phenotypic and epigenetic plasticity resulting in complex heterogenic diseases. In this review, we discuss the key principles of deregulation of epigenetic processes that shape this disease evolution. We consider measures to define and quantify clonal heterogeneity, combining information from recent studies assessing mutational, transcriptional and epigenetic landscapes at single cell resolution in Myeloid Neoplasms (MN). We highlight the importance of integrating epigenetic and genetic information to better understand inter‐ and intra‐patient heterogeneity and discuss how this understanding further informs evolution and progression trajectories and subsequent clinical response in MN. Under this topic, we also discuss efforts to identify mechanisms of resistance, by longitudinal analysis of patient samples. Finally, we highlight how we might target these aberrant epigenetic processes for better therapeutic outcomes and to potentially eradicate LSCs.

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Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia

Cited by 54 publications

References 39 publications

Rapid progression of myelofibrosis in polycythemia vera patient carrying SRSF2 c.284C>A p.(Pro95His) and unique ASXL1 splice site c.1720‐2A>G variant

Rapid progression of myelofibrosis in polycythemia vera patient carrying SRSF2 c.284C>A p.(Pro95His) and unique ASXL1 splice site c.1720‐2A>G variant

Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic

A guide to epigenetics in leukaemia stem cells

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