BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

to connected objects

Abstract: Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-XL inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy

Location
Deutsche Nationalbibliothek Frankfurt am Main
Extent
Online-Ressource
Language
Englisch
Notes
Leukemia. - 38, 1 (2024) , 136-148, ISSN: 1476-5551

Event
Veröffentlichung
(where)
Freiburg
(who)
Universität
(when)
2023
Creator

DOI
10.1038/s41375-023-02079-5
URN
urn:nbn:de:bsz:25-freidok-2412098
Rights
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Last update
25.03.2025, 1:56 PM CET

Data provider

This object is provided by:
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Show original at data provider

Associated

Time of origin

  • 2023

Other Objects (12)

Extrazelluläre Effekte des Ca2+-bindenden Proteins S100A1 : grundlegende Experimente zur Morphologie und Funktion neonataler Kardiomyozyten in Abhängigkeit der Kulturbedingungen

Hochschulschrift

Extrazelluläre Effekte des Ca2+-bindenden Proteins S100A1 : grundlegende Experimente zur Morphologie und Funktion neonataler Kardiomyozyten in Abhängigkeit der Kulturbedingungen

Das Verbundprojekt "Personalisierte Medizin für die Onkologie" (PM4Onco) als Teil der Medizininformatik-Initiative (MII) : = The collaborative project "Personalized medicine for oncology" (PM4Onco) as part of the Medical Informatics Initiative (MII)

Das Verbundprojekt "Personalisierte Medizin für die Onkologie" (PM4Onco) als Teil der Medizininformatik-Initiative (MII) : = The collaborative project "Personalized medicine for oncology" (PM4Onco) as part of the Medical Informatics Initiative (MII)

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells

Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells

CREBBP is a target of epigenetic, but not genetic, modification in juvenile myelomonocytic leukemia

CREBBP is a target of epigenetic, but not genetic, modification in juvenile myelomonocytic leukemia

Blind normalization of public high-throughput databases

Blind normalization of public high-throughput databases

Systems medicine in the scope of multi omics analyses

Hochschulschrift

Systems medicine in the scope of multi omics analyses

Molecular characterisation of tumours and biomarker identification for personalised radiation oncology using genomic data of patients with locally advanced head and neck squamous cell carcinoma

Molecular characterisation of tumours and biomarker identification for personalised radiation oncology using genomic data of patients with locally advanced head and neck squamous cell carcinoma

Current treatment of juvenile myelomonocytic leukemia

Current treatment of juvenile myelomonocytic leukemia

Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo

Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo

Sondersituation der Daten in der Onkologie : = Data complexity in oncology

Sondersituation der Daten in der Onkologie : = Data complexity in oncology

The impact of pre‐pregnancy folic acid intake on placental DNA methylation in a fortified cohort

The impact of pre‐pregnancy folic acid intake on placental DNA methylation in a fortified cohort

Related objects