Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community

Abstract

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

Fig. 1. Targetable mutations for menin inhibitors across age distribution in ALL and AML.

A Frequency of de novo KMT2A-r leukemias by age. (Data are from a series of 2381 prescreened acute leukemia patients analyzed by the Frankfurt Diagnostic Center of Acute Leukemia) [41]. B Estimated annual incidence of newly diagnosed and relapsed KMT2A-r ALL among infants and non-infants in COG studies. Note the distinct rates of relapse, ALL, acute lymphoblastic leukemia. C Breakdown of molecular subtypes of pediatric AML. Highlighted subtypes are associated with aberrant HOX/MEIS1 expression.

Fig. 2. KMT2A rearrangement leads to leukemogenesis.

A Interaction among KMT2A (MLL1), menin, and LEDGF. Menin binding sites are preserved during KMT2A rearrangement. B Cell differentiation and the gradual decrease of the HOX program. C The MLL1 fusion protein (MLL1-FP) leads to the overexpression of HOX cluster genes and MEIS1, contributing to the uncontrolled proliferation of undifferentiated precursor cells. D Novel synthesized menin inhibitors disrupt the menin-KMT2A interaction, effectively preventing the binding of MLL1-FP to promoter sites. This disruption halts the aberrant expression of HOX genes and MEIS1, resulting in the release of the differentiation block. Menin inhibitors disrupt NUP98 fusion occupancy at chromatin sites and disrupt MLL-NPM1 activity. This induces differentiation and reverses leukemogenesis by downregulating MEIS1 expression.

Fig. 3. Mechanisms of resistance to menin inhibition.

A Illustrates the mechanism of menin inhibition, showing how it interferes with the interaction between menin and KMT2A. This in turn prevents the aberrant expression of HOX genes and MEIS1, leading to the release of the differentiation block. B Somatic mutations in MEN1 hinder the displacement of the menin-MLL1 protein complex, thereby preventing the gene expression changes necessary to inhibit leukemic cell self-renewal and induce myeloid differentiation.

Fig. 4. Future combinations of menin inhibitors in pediatric leukemia.

Challenges in a diverse and small population.

Fig. 5. Estimated annual incidence of newly diagnosed and recurrent AML in pediatric patients globally and in the US.

A International study groups’ estimated annual incidences of newly diagnosed pediatric AML [78]. AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica; Italy), NOPHO-DB-SHIP (Nordic Society of Pediatric Hematology and Oncology; [Denmark, Finland, Iceland, Norway, and Sweden, Latvia, Lithuania, Estonia, the Netherlands, Belgium, Hong Kong, Spain, Portugal and Israel]), BFM (Berlin-Frankfurt-Münster Oncology; Austria, Czech Republic, Poland, Hungary, Slovakia, Slovenia, Croatia, Serbia, Bulgaria, Romania, and Turkey), MyeChild (United Kingdom), JCCG (Japan Children’s Cancer Group; Japan), COG (Children’s Oncology Group; United States and Canada), St. Jude (United States), B Estimated annual incidence of newly diagnosed and recurrent KMT2A-r AML among pediatric patients. C Estimated annual incidence of newly diagnosed and relapsed NPM1c and NUP98-r AML among pediatric patients in COG studies.