Mesenchymal Stem Cells in Low Risk Acute Myeloid Leukemia With Nucleophosmin Gene Mutation: a Study of the Tumor Microenvironment and Its Contribution to the Outcome

Background Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest of myeloid progenitor cells.

Although incomplete, current knowledge of AML pathogenesis has allowed patient stratification into different prognostic groups and has led to the emergence of personalized treatment strategies.

The European Leukemia Net (ELN) stratifies de novo AML into favorable, intermediate and adverse risk groups according to genetic mutations and chromosomal abnormalities. In particular, patients with a favorable-risk profile are characterized by either the presence of core-binding factor rearrangements (CBF), normal karyotype with nucleophosmin 1 (NPM1) mutations and fms related receptor tyrosine kinase 3 (FLT3) wild-type, NPM1 mutations and FLT3-internal tandem duplication with low allelic ratio, or biallelic mutations in CCAAT/enhancer binding protein α (CEBPα).

Despite the favorable-risk profile, patients in long-term follow-up after conventional chemotherapy have relapse rates of up to 50% in AML with NPM1 mutation, 40% in CBF AML, and 44% in AML with CEBPα biallelic mutation. These data highlight the need for further investigation among favorable-risk AML to gain more knowledge regarding the pathogenetic and resistance mechanisms, thus improving patient stratification. Moreover, these insights could lead to the discovery of new therapeutic targets.

NPM1 is the most frequent mutation in AML, accounting for approximately 50-60% of de novo cytogenetically normal AML. Murine and in vivo studies have demonstrated that NPM1 mutation promotes leukemogenesis and myeloproliferation but is not sufficient to induce leukemia. Pre-existing mutations of hematopoietic stem cells (HSCs) may be a possible mechanism that cooperates in leukemogenesis. These mutations mainly involve epigenetic modifiers in hematopoietic stem or progenitor cells, resulting in their clonal expansion in individuals without an overt hematologic disease. This condition, named clonal hematopoiesis, represents a pre-leukemic state that may promote the emergence of mutations able to drive leukemogenesis. Indeed, NPM1 mutations frequently cluster with co-occurring mutations involving genes of the signaling pathways, DNA methylation, RNA-splicing, cohesin complex, gene transcription, and tumor suppression.