Dysregulation of HOXA genes in acute myeloid leukemia and targeted therapy

The abnormal expression of the HOXA genes is intricately associated with the pathogenesis and progression of acute myeloid leukemia (AML), as these genes are crucial in regulating cellular differentiation and proliferation during normal hematopoiesis. In normal hematopoiesis, the expression of HOXA genes is meticulously regulated by the interplay between activation by the KMT2A complex or CDX and repression by the PRC2 complex. AML disrupts this balance, resulting in the persistent activation of HOXA. They perpetuate a leukemic state by directly activating a network of downstream target genes, which facilitate proliferation, hinder differentiation, and inhibit apoptosis. Genetically, this dysregulation can be classified as KMT2A-dependent, as shown in KMT2A rearrangements, NPM1 mutations, NUP98 rearrangements and other type of acute myeloid leukemia. Menin inhibitors may be employed for the dysregulation of HOXA genes reliant on them. Although menin inhibitors have considerable therapeutic efficacy, issues such as drug resistance and particular toxicity still require resolution. Diverse targeted therapeutics may be accessible for the dysregulation of non-KMT2A-dependent HOXA genes, contingent upon the specific genetic alterations. Therefore, a comprehensive understanding of the HOXA signaling network is vital for advancing targeted AML treatments.