High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia

Aid, Zakia; Robert, Estelle; Lopez, Cécile K.; Bourgoin, Maxence; Boudia, Fabien; Mene, Melchior Le; Rivière, Julie; Baille, Marie; Benbarche, Salima; Renou, Laurent; Fagnan, Alexandre; Thirant, Cécile; Federici, Laetitia; Touchard, Laure; Jetten, Anton M.; Geoerger, Birgit; Lapillonne, Hélène; Solary, Éric; Gaudry, Muriel; Meshinchi, Soheil; Pflumio, Françoise; Auberger, Patrick; Lobry, Camille; Petit, Arnaud; Jacquel, Arnaud; Mercher, Thomas

doi:10.1038/s41375-022-01800-0

Cited by 6 publications

(3 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In three distinct murine models of AMKL carrying CBFA2T3::GLIS2 alone, in combination with JAK2 p.V617F, or with copy number alterations on chromosome 21, ruxolitinib significantly prolongs survival, justifying its therapeutic testing in pediatric AMKL ( Drenberg et al, 2019 ). A new study showed that patient-derived CBFA2T3::GLIS2 -positive AMKL cells express high levels of pro-apoptotic CASP3 and anti-apoptotic BCL2 ( Aid et al, 2023 ). CBFA2T3::GLIS2 -positive cell lines are dependent on BCL2 family members for cell survival.…”

Section: Novel Molecularly Targeted Therapeutic Strategies Being Deve...mentioning

confidence: 99%

“…CBFA2T3::GLIS2 -positive cell lines are dependent on BCL2 family members for cell survival. Combined targeting of BCL2 (using ABT199) and the myeloid cell lymphoma-1 (MCL1) protein (using S63845 ) inhibits the proliferation of CBFA2T3::GLIS2 cells in vitro and abrogates leukemia progression in mouse xenografts ( Aid et al, 2023 ). Another pro-survival protein BCL-xL was also identified as a potential therapeutic vulnerability in erythroid and megakaryocytic lineage leukemias, including in the M07e AMKL cell line harboring CBFA2T3::GLIS2 ( Kuusanmaki et al, 2023 ).…”

Section: Novel Molecularly Targeted Therapeutic Strategies Being Deve...mentioning

confidence: 99%

“…Fusion protein GLIS2 (Masetti et al, 2017) KDM5A (PHD domain) (Michmerhuizen et al, 2020) Protein-protein interactions Interaction between KMT2A and menin (Krivtsov et al, 2019;Klossowski et al, 2020); Interaction between KMT2A fusion partners and DOT1 (Yi and Ge, 2022) Interaction between KMT2A and menin (Heikamp et al, 2022) Downstream molecules or pathways CD56 (Smith et al, 2020); Super enhancer, KIT and PDGFRA (Benbarche et al, 2022); FOLR1 (Le et al, 2022); BCL2 family members (e.g., BCL2, MCL1, BCL-xL) (Aid et al, 2023;Kuusanmaki et al, 2023) CDK6 (Placke et al, 2014;Schmoellerl et al, 2020); HOXA (de Rooij et al, 2017) CDK6 (Schmoellerl et al, 2020); JAK (Cardin et al, 2019;Noort et al, 2021); HOXA and HOXB (Noort et al, 2021) Co-occurring mutations RAS mutations (de Rooij et al, 2017;Mansur et al, 2017;Chu et al, 2018) RB1 loss (de Rooij et al, 2017) Other potential targets Aurora A (Thiollier et al, 2012) IKAROS (Aubrey et al, 2022); LIM (Jensen et al, 2020) Targeting interactions of the driver fusion with its associated molecules is another way to inhibit its leukemogenic drive. For instance, KMT2A directly binds to menin through the MBD domain and forms a menin-KMT2A complex.…”

Section: Gata1 Mutationsmentioning

confidence: 99%

See 2 more Smart Citations

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

Kalev‐Zylinska

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) in which leukemic blasts have megakaryocytic features. AMKL makes up 4%–15% of newly diagnosed pediatric AML, typically affecting young children (less than 2 years old). AMKL associated with Down syndrome (DS) shows GATA1 mutations and has a favorable prognosis. In contrast, AMKL in children without DS is often associated with recurrent and mutually exclusive chimeric fusion genes and has an unfavorable prognosis. This review mainly summarizes the unique features of pediatric non-DS AMKL and highlights the development of novel therapies for high-risk patients. Due to the rarity of pediatric AMKL, large-scale multi-center studies are needed to progress molecular characterization of this disease. Better disease models are also required to test leukemogenic mechanisms and emerging therapies.

show abstract

Section: Novel Molecularly Targeted Therapeutic Strategies Being Deve...mentioning

confidence: 99%

Section: Novel Molecularly Targeted Therapeutic Strategies Being Deve...mentioning

confidence: 99%

Section: Gata1 Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

Kalev‐Zylinska

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax

Neault,

Lebert-Ghali,

Fournier

et al. 2023

Cell Reports

View full text Add to dashboard Cite

CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia is sensitive to BCL-XL inhibition by navitoclax and DT2216

Gress,

Roussy,

Boulianne

et al. 2023

Blood Advances

View full text Add to dashboard Cite

Acute megakaryoblastic leukemia (AMKL) is a rare, developmentally restricted and highly lethal cancer of early childhood. The paucity and hypocellularity (due to myelofibrosis) of primary patient samples hamper the discovery of cell- and genotype-specific treatments. AMKL is driven by mutually exclusive chimeric fusion oncogenes in two thirds of cases, with CBFA2T3::GLIS2 (CG2) and NUP98 fusions (NUP98r) representing the highest fatality subgroups. We established CD34+ cord blood-derived CG2 models (n=6) that sustain serial transplantation and recapitulate human leukemia regarding immunophenotype, leukemia initiating cell frequencies, co-mutational landscape and gene expression signature with distinct upregulation of the pro-survival factor BCL2. Cell membrane proteomic analyses highlighted CG2 surface markers preferentially expressed on leukemic cells compared to CD34+ cells (e.g. NCAM1, CD151). AMKL differentiation block in the mega-erythroid progenitor space was confirmed by single cell profiling. While CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with Venetoclax, they were vulnerable to strategies that target the megakaryocytic pro-survival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor Navitoclax and DT2216, a selective BCL-XL PROTAC (proteolysis-targeting chimera) degrader developed to limit thrombocytopenia in patients. NUP98r AMKL were also sensitive to BCL-XL inhibition, but not the NUP98r monocytic leukemia, pointing to a lineage-specific dependency. Navitoclax or DT2216 treatment in combination with low dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL.

show abstract

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia

Cited by 6 publications

References 54 publications

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax

CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia is sensitive to BCL-XL inhibition by navitoclax and DT2216

Contact Info

Product

Resources

About