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IT’S TIME TO CONSIDER

THE IMPACT OF THE

MENIN PATHWAY1

IT’S TIME TO CONSIDER THE

IMPACT OF THE

MENIN PATHWAY1

The menin pathway may play a critical role

The menin pathway may play a critical role in up to

in up to

50%

of
AMLs1-7

of AMLs1-7

Menin-dependent AML: a complex challenge

Among the complex circuitry of AML signaling systems, the menin pathway is thought to have a far-reaching impact on AML development and outcomes.1-5,8
The menin pathway is a crucial mediator in gene expression driving leukemogenesis1,2,4,8,9
Image of a circuit board representing the Menin Pathway
The menin pathway is a complex intracellular communication system that is most commonly activated by NPM1m or KMT2Ar. It is also associated with several other genetic alterations.1-3,10-13
When menin interacts with upstream genomic alterations, such as NPM1m and KMT2Ar, it drives downstream changes in gene expression, initiating leukemogenesis.1,2,9
Emerging research suggests that targeting upstream menin-dependent mutations, such as NPM1m, may also affect downstream secondary mutations, such as FLT3-ITD and IDH1/2.1,4,10-13
This may be a notable opportunity for patients with co-mutated AML, such as the common NPM1-m/FLT3-ITD or NPM1-m/IDH1/2 combinations.3,4,a
aAmong cases of NPM1-m AML, 39% are co-mutated with FLT3-ITD and 25% are co-mutated with IDH1/2.14,15

aAmong cases of NPM1-m AML, 39% are co-
  mutated with FLT3-ITD and 25% are co-
  mutated with IDH1/2.14,15

image of a circuit board representing menindependent mutations
By decoding the mechanisms through which menin affects leukemic cell behavior, it is possible to enhance the understanding of menin-dependent AMLs and potentially contribute to the broader landscape of AML treatment.1,2,4

Exploring the menin pathway may offer new insights into therapeutic strategies for NPM1-m AML1,2

Research in NPM1-m AML suggests that the upstream inhibition of the menin complex may reduce the expression of oncogenic genes, such as HOXA9/MEIS1, and may facilitate the differentiation of immature myeloid blasts into functional white blood cells. This inhibits the cell to proliferate and allows leukemic cells to undergo programmed cell death.4,16

A better understanding of the relationship between menin and NPM1m may be key to potentially changing outcomes for these patients.2

Patients with the most common menin-dependent AML, NPM1-m, continue to experience poor outcomes at relapse.3,14,17

Explore challenges
in NPM1-m AML

AML, acute myeloid leukemia; KMT2A-r, rearranged histone-lysine N-methyltransferase 2A; KMT2Ar, histone-lysine N-methyltransferase 2A rearrangement; NPM1-m, mutated nucleophosmin 1; NPM1m, nucleophosmin 1 mutation.

References

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References

1. Burrows F, Wu T, Kessler L, et al. A novel small molecule menin-MLL inhibitor for potential treatment of MLL-rearranged leukemias and NPM1/DNMT3A-mutant AML. Poster presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications; October 26-30, 2017; Philadelphia, PA. 2. Candoni A, Coppola G. A 2024 update on menin inhibitors. A new class of target agents against KMT2A-rearranged and NPM1-mutated acute myeloid leukemia. Hematol Rep. 2024;16(2):244-254. doi:10.3390/ hematolrep16020024 3. Falini B, Dillon R. Criteria for diagnosis and molecular monitoring of NPM1-mutated AML. Blood Cancer Discov. 2024;5(1):8-20. doi:10.1158/2643-3230.BCD-23-0144 4. Issa GC, Ravandi F, DiNardo CD, Jabbour E, Kantarjian HM, Andreeff M. Therapeutic implications of menin inhibition in acute leukemias. Leukemia. 2021;35(9):2482-2495. doi:10.1038/s41375-021-01309-y 5. Bertrums EJM, Smith JL, Harmon L, et al. Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia. Haematologica. 2023;108(8):2044-2058. doi:10.3324/haematol.2022.281653 6. National Cancer Institute. Acute myeloid leukemia with inv(3) (q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM. Accessed October 22, 2024. https://seer.cancer.gov/ seertools/hemelymph/ 51f6cf59e3e27c3994bd547d/ 7. National Cancer Institute. Acute myeloid leukemia with mutated RUNX1. Accessed October 22, 2024. https://seer.cancer.gov/seertools/ hemelymph/5a7e288d1ef557f9c8636d31/ 8. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013;38(8):394-402. doi:10.1016/j.tibs.2013.05.005 9. Falini B, Brunetti L, Sportoletti P, Martelli MP. NPM1-mutated acute myeloid leukemia: from bench to bedside. Blood. 2020;136(15):1707-1721. doi:10.1182/blood.2019004226 10. Collins CT, Hess JL. Deregulation of the HOXA9/MEIS1 axis in acute leukemia. Curr Opin Hematol. 2016;23(4):354-361. doi:10.1097/MOH.0000000000000245 11. Lu R, Wang P, Parton T, et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell. 2016;30(1):92-107. doi:10.1016/j.ccell.2016.05.008 12. Wang GG, Pasillas MP, Kamps MP. Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with Pbx and a novel function of the Meis1 C-terminus. Blood. 2005;106(1):254-264. doi:10.1182/blood-2004-12-4664 13. Chowdhury R, Yeoh KK, Tian Y-M, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463-469. doi:10.1038/embor.2011.43 14. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221. doi:10.1056/NEJMoa1516192 15. Sharma N, Liesveld JL. NPM 1 mutations in AML—the landscape in 2023. Cancers (Basel). 2023;15(4):1177. doi:10.3390/ cancers15041177 16. Uckelmann HJ, Haarer EL, Takeda R, et al. Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia. Cancer Discov. 2023;13(3):746-765. doi:10.1158/2159-8290.CD-22-0366 17. Issa GC, Bidikian A, Venugopal S, et al. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. 2023;7(6):933-942. doi:10.1182/ bloodadvances.2022008316

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