Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia
Abstract
:1. Introduction
2. Results
2.1. Susceptibility of AML Cell Lines Grown in the Absence or Presence of HS-5 Stroma Cells to AC-4-130 and Venetoclax
2.2. AC-4-130 Combination Treatment in AML Cell Lines
2.3. Changed Susceptibility of AML Cell Lines to Combination Treatment with AC-4-130 in the Presence of Bone Marrow Stroma
2.4. Induction of Apoptosis and Cell Death in AML Cell Lines
2.5. AC-4-140 Combination Treatments in Leukemic Cells In Vitro
3. Discussion
4. Materials and Methods
4.1. Patient Samples
4.2. Cell Lines and Cell Culture
4.3. Cytotoxicity Assays
4.4. Measurement of mRNA Expression by qPCR
4.5. Antibodies and Cytometry
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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ID | FAB | Origin | FLT3 | TP53 | Gene Variants | Karyotype |
---|---|---|---|---|---|---|
HL-60 | M2 | de novo | wt | null | CDKN2A R80X NRAS Q61L | hypotetraploid |
ML-2 | M4 | de novo | wt | wt | KMT2A-AFDN KRAS A146T | t(6;11) |
MOLM-13 | M5a, relapse | MDS | ITD | wt | KMT2A-MLLT3 | t(9;11) |
MOLM-16 | M0, relapse | de novo | wt | V173M C238S | MLL V1368L MTOR T571K | hypotetraploid |
OCI-AML3 | M4 | de novo | wt | wt | NRAS Q61L NPM1 L287fs DNMT3A R882C | +1, +5, +8 |
SKM-1 | M5, refractory | MDS | wt | R248Q R248Q | ASXL1 Y591X KRAS K117N TET2 C1419fs | del9q12 |
AML Cell Line | HS-5 Stroma | AC-4-130 +PTC596 | AC-4-130 +Trametinib | AC-4-130 +S63845 | AC-4-130 +PKC412 | AC-4-130 +Venetoclax |
---|---|---|---|---|---|---|
SKM-1 | absent | 0.6–0.8 | 0.6–0.8 | 0.7–0.9 | nd | 0.4–0.6 |
present | 1.0–1.2 | 0.8–1.0 | 1.1–1.3 | nd | 0.5–0.7 | |
MOLM-13 | absent | 0.9–1.1 | 1.2–1.7 | 0.8–1.0 | 0.4–0.6 | 0.6–0.8 |
present | 0.6–0.8 | nc | 0.8–1.0 | 0.4–0.6 | 0.8–0.9 |
ID | Disease | FAB | Antecedent | Gene Variants | Karyotype | AC+S * |
---|---|---|---|---|---|---|
AML1 | sAML | M0 | MDS | EVI1 (overexpressed) | −7 | NR |
AML2 | AML | M0 | TP53 (VAF 92%) | complex | NR | |
AML3 | sAML | MDS | CEPBA, ASXL1, EZH2, RUNX1 | normal | NR | |
AML4 | sAML | ET | ASXL1, CALR, KMT2A (amp), TP53 (VAF 50%), | 49, +der(11) | NR | |
AML5 | AML | M5 | FLT3-TKD (0.63), NPM1, DNMT3A | normal | SR | |
AML6 | sAML | M4 | bicytopenia | NPM1,FLT3-TKD (0.57), TET2, TP53 (VAF 5%), SRSF2 | +8 | SR |
AML7 | AML | M5 | ASXL1, TET2, KRAS, SH2B3, U2AF1 | −7 | SR | |
AML8 | AML | M5 | FLT3-ITD (0.58), NPM1, DNMT3A | normal | SR | |
AML9 | sAML | M1 | MDS | NPM1, TET2, DNMT3A | normal | SR |
AML10 | AML | M1 | FLT3-ITD (0.833), NPM1 | normal | SR | |
AML11 | AML | M2 | normal | complex, −7,−9 | NR | |
AML12 | sAML | MPN | JAK2 | normal | NR | |
AML13 | sAML | M4 | breast cancer | NPM1, TET2 | normal | SR |
AML14 | AML | M1 | FLT3-ITD (>1.0), NPM1 | normal | SR | |
AML15 | AML | M4 | FLT3-ITD (0.504), NPM1 | normal | SR | |
AML16 | AML | M2 | NPM1, IDH2, DNMT3A | normal | SR | |
AML17 | AML | M1 | FLT-3-ITD (0.783), BCOR, TET2, U2AF1 | del20q11, +8 | SR | |
AML18 | AML | M4 | FLT3-TKD (0.487), NRAS, KRAS, KMT2A-MLLT10 | t(10;11), +8 | SR | |
MDS1 | MDS | TET2, ETV6, KRAS, SRSF2, CBL | del7q | SR | ||
BA1 | B-ALL | IGH (rearranged) | normal | NR | ||
BA2 | B-ALL | normal | normal | SR | ||
CML1 | CML | BCR-ABL1 | t(9;22) | NR | ||
MM1 | MM | normal | NR | |||
MM2 | MM | t(4;14) | NR | |||
HD | n.a. | normal | normal | NR |
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Seipel, K.; Graber, C.; Flückiger, L.; Bacher, U.; Pabst, T. Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia. Int. J. Mol. Sci. 2021, 22, 8092. https://doi.org/10.3390/ijms22158092
Seipel K, Graber C, Flückiger L, Bacher U, Pabst T. Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia. International Journal of Molecular Sciences. 2021; 22(15):8092. https://doi.org/10.3390/ijms22158092
Chicago/Turabian StyleSeipel, Katja, Carolyn Graber, Laura Flückiger, Ulrike Bacher, and Thomas Pabst. 2021. "Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia" International Journal of Molecular Sciences 22, no. 15: 8092. https://doi.org/10.3390/ijms22158092