Targeting apoptosis dysregulation in myeloid malignancies - The promise of a therapeutic revolution

Santinelli, Enrico; Pascale, Maria Rosaria; Xie, Zhuoer; Badar, Talha; Stahl, Maximilian F.; Bewersdorf, Jan P.; Gurnari, Carmelo; Zeidan, Amer M.

doi:10.1016/j.blre.2023.101130

Cited by 4 publications

(3 citation statements)

References 200 publications

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“… 48 More recently the Menin/MLL inhibitor revumenib (SNDX‐5613) showed promising results against the HOXA9‐dependant MLL subtypes of AML, 6 , 49 but it also led to resistance. 50 Overcoming this resistance and other expected ones will require new drugs, 3 , 4 with one approach being the direct targeting of HOXA9 function as a common downstream effector of differentiation blockade. 10 HOXA9 is an interesting oncogenic target since it is not or only slightly expressed in healthy adult tissues, except in hematopoietic stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…Among approved or clinically tested targeted therapies are FLT3-mutated, P53-mutated, IDH-mutated or BCL2 inhibitors, cereblon E3-ligase modulators, and monoclonal antibodies (anti-CD33, CD123 ± CD3, CD47, CTLA4, PD-1, or TIM3). 3,4 Additionally, the development of small molecule inhibitors aiming to induce AML cell differentiation to mirror the success of all-trans-retinoic-acid (ATRA/Tretinoïne/Vesanoid®) and arsenic trioxide (ATO/Trisenox®) targeting the PML-RARα fusion transcription factor in acute promyelocytic leukemia (APL, AML-M3) is an attractive strategy leading to the development of IDH1 (Ivosidenib/AG-120/Tibsovo®) or IDH2 (Enasidenib/AG-221/Idhifa®) mutants inhibitors, or epigenetic modulators against the menin/MLL interaction like Revumenib/SNDX-5613, Ziftomenib/KO-539 or JNJ-6617, or targeting DOT1L histone methyltransferase (Pinometostat/EPZ-5676). [5][6][7] While transcription factors play a key role in regulating the expression of oncogenic-associated genes, the direct targeting of these factors by antitumor molecules remains limited.…”

Section: Introductionmentioning

confidence: 99%

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Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Lambert,

Jambon,

Bouhlel

et al. 2024

HemaSphere

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The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP‐1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient‐derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Lambert,

Jambon,

Bouhlel

et al. 2024

HemaSphere

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“…The analysis of the association between PIP4K2 genes and sensitivity to antineoplastic drugs in ex vivo assays in AML identified targets of clinical importance in hematological malignancies, including ABL1, EGFR, VEGFR, AKT, ERK, BCL2, and FLT3 [20][21][22][23][24]. In the present study, we chose to evaluate the combination of THZ-P1-2 and venetoclax in different AML models.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia

Lima,

Carvalho,

Pereira-Martins

et al. 2023

IJMS

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Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.

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Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells

Khan,

Al-Tamimi,

Anver

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Targeting apoptosis dysregulation in myeloid malignancies - The promise of a therapeutic revolution

Cited by 4 publications

References 200 publications

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia

Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells

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