Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring &lt;i&gt;STAG2&lt;/i&gt; mutations

Subramaniam, Agatheeswaran; Sandén, Carl; Moura-Castro, Larissa H.; Žemaitis, Kristijonas; Schmiderer, Ludwig; Baudet, Aurélie; Bäckström, Alexandra; Arvidsson, Elin; Hultmark, Simon; Miharada, Natsumi; Magnusson, Mattias; Paulsson, Kajsa; Fioretos, Thoas; Larsson, Jonas

doi:10.3324/haematol.2021.280303

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…Cancer cells depend on the overlapping function of STAG1 in STAG2 knockout cell lines to maintain the integrity of chromatin cohesion; double knockout of STAG1 and STAG2 induces synthetic lethality [ 79 ]. Recently, investigators performed a proof-of-concept demonstration in primary human leukemic cells: disrupting STAG1 eliminated STAG2 mut AML cells and was well tolerated by wild-type hematopoietic stem cells [ 80 ]. These findings pave the way for the evaluation of STAG1 inhibition for the treatment of STAG2 mut AML.…”

Section: Aberrations Of Chromatin Modifiersmentioning

confidence: 99%

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Bouligny

Maher

Grant

2023

Cancers

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The characterization of the molecular landscape and the advent of targeted therapies have defined a new era in the prognostication and treatment of acute myeloid leukemia. Recent revisions in the European LeukemiaNet 2022 guidelines have refined the molecular, cytogenetic, and treatment-related boundaries between myelodysplastic neoplasms (MDS) and AML. This review details the molecular mechanisms and cellular pathways of myeloid maturation aberrancies contributing to dysplasia and leukemogenesis, focusing on recent molecular categories introduced in ELN 2022. We provide insights into novel and rational therapeutic combination strategies that exploit mechanisms of leukemogenesis, highlighting the underpinnings of splicing factors, the cohesin complex, and chromatin remodeling. Areas of interest for future research are summarized, and we emphasize approaches designed to advance existing treatment strategies.

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Section: Aberrations Of Chromatin Modifiersmentioning

confidence: 99%

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Bouligny

Maher

Grant

2023

Cancers

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Dynamics of measurable residual disease for risk stratification and guiding allogeneic transplant in acute myeloid leukaemia patients with myelodysplasia‐related mutations in first remission

Jiang,

Cheng,

Sun

et al. 2024

Br J Haematol

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SummaryAccurate classification and risk prediction are critical for therapeutic decision‐making in patients with acute myeloid leukaemia (AML). Myelodysplasia‐related (MR) gene mutations are classified as adverse genetic factors by the European LeukaemiaNet‐2022 guidelines. However, their prognostic value in de novo AML remains controversial. This study retrospectively analysed 188 patients with de novo AML‐MR, stratifying them into four subgroups based on dynamic measurable residual disease (MRD) after induction, one or two courses of consolidation chemotherapy. The median follow‐up was 36.8 months (4.6–73.7). Patients with persistent or recurrent MRD positivity after the second consolidation had the poorest 3‐year relapse‐free survival (RFS), overall survival (OS) and cumulative incidence of relapse compared to the other groups (p < 0.001). Multivariable analysis identified this high‐risk group as an independent risk factor for both RFS and OS. We observed significant heterogeneity of OS benefit from allogeneic stem cell transplantation (allo‐SCT) by MRD‐risk groups, with substantial OS advantage for patients in subgroup D (3‐year OS: allo‐SCT 70.0% vs. 18.2% without, p < 0.001) but no benefit for others (p = 0.047 for interaction). This study underscores the importance of dynamic MRD in refining risk stratification and identifying de novo AML patients with MR mutations who would benefit from allo‐SCT during the first complete remission.

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Paralog-based synthetic lethality: rationales and applications

Xin¹,

Zhang²

2023

Front. Oncol.

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Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed. Paralogs, a set of homologous genes that have diverged from each other as a consequence of gene duplication, make the concept of SL feasible as the loss of one gene does not affect the cell’s survival. Furthermore, homozygous loss of paralogs in tumor cells is more frequent than singletons, making them ideal SL targets. Although high-throughput CRISPR-Cas9 screenings have uncovered numerous paralog-based SL pairs, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors that exclusively target a single but not both paralogs hinder further clinical development. Here, we review the potential mechanisms of paralog-based SL given their function and genetic combination, and discuss the challenge and application prospects of paralog-based SL in cancer therapeutic discovery.

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Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring <i>STAG2</i> mutations

Abstract: Not available.

Cited by 3 publications

References 16 publications

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Dynamics of measurable residual disease for risk stratification and guiding allogeneic transplant in acute myeloid leukaemia patients with myelodysplasia‐related mutations in first remission

Paralog-based synthetic lethality: rationales and applications

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