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NPM1m AML and KMT2Ar AML/ALL are acute leukemia subtypes that share a common dependency on the menin-KMT2A interaction.2
NPM1 mutations are acquired driver mutations that play a critical role in the pathogenesis of NPM1m AML.3,4 NPM1 mutations are the most common genetic alteration in adult AML cases, and prognosis after relapse is poor.4,5
NPM1 mutations are found in ~35% of patients with AML4,6
<50% 5-year overall survival7
Relapsed/refractory NPM1m AML is an acute leukemia with a critical unmet need
KMT2Ar acute leukemias are associated with a very poor prognosis and high relapse rates.2 KMT2Ar AML/ALL are aggressive diseases that span multiple age groups and phenotypes.2
KMT2Ar occurs in ~10% of adult AML/ALL cases and ~80% of infant ALL cases2
<25%
5-year overall survival2,7
(adult acute leukemias)
KMT2Ar AML/ALL are acute leukemias with a critical unmet need
Current guidelines recommend testing for NPM1 mutations and KMT2A rearrangements as part of the diagnostic workup of acute leukemia6
Novel therapies are urgently needed as there are currently no approved treatments that selectively target the underlying disease mechanisms driving these specific acute leukemias1,3
A closer look at the role of menin in NPM1m and KMT2Ar acute leukemias reveals a potential targetable pathway to investigate further.
NPM1m AML and KMT2Ar AML/ALL are acute leukemia subtypes that share a strong HOX/MEIS1 gene expression pattern with a common dependency on the menin-KMT2A interaction.2
In NPM1m AML, nuclear NPM1m binds to chromatin and abnormally exposes transcription start sites for menin-KMT2A binding, leading to upregulation of HOX/MEIS1 gene expression, resulting in leukemogenesis.8
Menin interactions modify chromatin, allowing the menin-KMT2A complex to drive increased expression of HOX and MEIS1 genes2,8
Upregulation of HOX/MEIS1 gene expression promotes leukemogenesis2,8
Increased proliferation of undifferentiated cells results in acute leukemia2,8
In KMT2Ar acute leukemias, menin
In NPM1m AML, menin interacts with
Menin interactions modify chromatin, allowing the menin-KMT2A complex to drive increased expression of HOX and MEIS1 genes2,8
Upregulation of HOX/MEIS1 gene expression promotes leukemogenesis2,8
Increased proliferation of undifferentiated cells results in acute leukemia2,8
With a deeper understanding of the mechanisms that contribute to these specific leukemias, the menin-KMT2A interaction becomes an intriguing target to investigate.
Clinical research into the disruption
of menin-KMT2A
interactions
is ongoing
ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; HOX=homeobox; KMT2A=lysine methyltransferase 2A; KMT2Ar=lysine methyltransferase 2A rearranged; MEIS1=MEIS homeobox-1; MLL1=mixed-lineage leukemia protein-1; NPM1m=mutant nucleophosmin-1.
References: 1. Li X, Song Y. J Hematol Oncol. 2021;14:56. 2. Issa GC, et al. Leukemia. 2021;35:2482-2495. 3. Falini B. Am J Hematol. 2023;98(9):1452-1464. 4. Ranieri R, et al. Leukemia. 2022;36(10):2351-2367. 5. Kuhn MWM, et al. Cancer Discov. 2016;6:1166-1181.
6. Arber DA, et al. Arch Pathol Lab Med . 2017;141:1342-1393. 7. Stein E, Aldoss I, DiPersio J, et al. Slides presented at the American Society of Hematology Annual Meeting, Atlanta, GA (2021, December). 8. Uckelmann H, et al. Cancer Discov. 2023;13(3):746-765. 9. Yokoyama A, et al. Cell. 2005;123:207-218. 10. Uckelmann H, et al. Science. 2020;367:586-590.
