Targeting GOF Mutations in Leukemia: FLT3 and NOTCH1

Gain-of-function (GOF) mutations are genetic alterations that result in a new, enhanced, or altered molecular function or gene expression. Such mutations often lead to overactive proteins that drive cancer progression.¹ Understanding GOF mutations is crucial for developing targeted therapies which inhibit the activity of aberrant proteins. Here, we explored FLT3 and NOTCH1 as GOF mutations associated with leukemia.

Leukemia, a cancer of blood and bone marrow, results from abnormal white blood cell (WBC) production. An excess of WBCs, termed leukocytosis, hinders the production of vital blood cells needed for oxygen-transport, fighting infections and blood clotting. GOF mutations in leukemia often involve genes encoding proteins with roles in cell growth and survival.² Identifying these mutations holds promise in oncology, paving the way for targeted and effective treatments.

Causaly can be used to identify potential targets with GOF mutations in a disease. Over 200 targets with GOF mutations were uncovered by Causaly. Around 100 of these targets were found to be involved in leukemia progression. Two of the most studied targets associated with leukemia progression were FLT3 and NOTCH1.

FLT3, a receptor tyrosine kinase, plays a pivotal role in leukemia. Mutations in the FLT3 gene are the most common genetic alterations associated with Acute Myeloid Leukemia (AML).³ In leukemia, GOF mutations in FLT3 cause uncontrolled cell proliferation, leading to cancer progression.

GOF mutations in FLT3 result in continuous activation of tyrosine kinase. A recent study also showed that GOF kinase mutations in AML induced intracellular alkalization.⁴ FLT3 was highlighted as one of the kinases that phosphorylate NHE1, leading to alkaline intracellular pH and supporting the survival of AML cells.⁴  Targeting of this mechanism, specifically through sodium/hydrogen exchanger therefore may offer potential therapeutic benefits.

NOTCH1, a transmembrane receptor protein, plays a role in regulating biological processes, including cell specialization and angiogenesis. In leukemia, mutations in the NOTCH1 gene lead to uncontrolled cell growth, disrupted differentiation, and resistance to apoptosis.⁵ GOF mutations in NOTCH1 are present in 55% of childhood T-cell Acute Lymphoblastic Leukemia cases.⁶

GOF mutations in NOTCH1, along with pre-TCR signaling and HEB protein downregulation, drives disease progression.⁷ This gene has also shown significance in the reprogramming of thymocytes (immune cells in the thymus). Notably, hyperactive NOTCH1 can sensitize immature thymocytes to other mutations and thus, requires collaboration with other factors to drive disease progression.⁸

GOF mutations can contribute to disease aggressiveness, causing uncontrolled tumor growth and survival. Understanding the intricate role of these mutations is important for the development of targeted therapies. In this use case, FLT3 and NOTCH1 were explored as targets with GOF mutations in leukemia. Inhibitors targeting these proteins have shown promising results in leukemia treatment. For example, FLT3 inhibitor quizartinib was recently FDA-approved for patients with FLT3-mutated AML.⁹ This underscores the potential of targeted therapies in revolutionizing the treatment landscape for leukemia patients.