MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common kind of pediatric cancer. Although the cure rates in ALL have significantly increased in developed countries, still 15-20% of patients relapse, with even higher rates in developing countries. The role of non-coding RNA genes as microRNAs (miRNAs) has gained interest from researchers in regard to improving our knowledge of the molecular mechanisms underlying ALL development, as well as identifying biomarkers with clinical relevance. Despite the wide heterogeneity reveled in miRNA studies in ALL, consistent findings give us confidence that miRNAs could be useful to discriminate between leukemia linages, immunophenotypes, molecular groups, high-risk-for-relapse groups, and poor/good responders to chemotherapy. For instance, miR-125b has been associated with prognosis and chemoresistance in ALL, miR-21 has an oncogenic role in lymphoid malignancies, and the miR-181 family can act either as a oncomiR or tumor suppressor in several hematological malignancies. However, few of these studies have explored the molecular interplay between miRNAs and their targeted genes. This review aims to state the different ways in which miRNAs could be involved in ALL and their clinical implications.

Keywords: ALL subtypes; acute lymphoblastic leukemia; hematopoiesis; miRNA biomarkers; miRNAs.

Figure 1

MiRNA biogenesis pathways. Schematic diagram of the canonical and non-canonical miRNA biogenesis process. In the canonical pathway, a primary miRNA transcript produced by RNA polymerase II is processed by the Drosha microprocessor in the nucleus. The generated pre-miRNA is transported to the cytoplasm in an EXP5-Ran GT-dependent manner and further processed by the Dicer microprocessor to generate a mature miRNA. The mature miRNA is loaded onto RISC to inhibit the translation of a target mRNA to conduct degradation. The non-canonical pathway is Drosha or Dicer dependent. AGO2, Argonaut protein 2; DGCR8, DiGeorge critical region 8; EXP5, exportin-5; RISC, RNA-induced silencing complex; XPO1, exportin-1.

Figure 2

The miRNAs potentially implicated in hematopoiesis and leukemogenesis. (A) Hematopoiesis process is schematized, and examples of miRNAs expressed involved in the cell differentiation and maturation are indicated. (B) The miRNAs with dysregulated expression that are potentially involved in oncogenic lymphoblast transformation and progression are shown. MiRNAs in red means downregulation, and miRNAs in green means upregulation; HSCs, hematopoietic stem cells; MPP, multipotent progenitors; CLP, common lymphoid progenitors; CMP, common myeloid progenitors; CFU-G, granulocytic colony-forming unit.

Figure 3

SNPs’ functional effect on miRNAs’ activity. Gene localization of SNPs will determine the effect on miRNA activity. (A) SNPs located in the promoter region could modify the expression levels of the mature miRNA, altering the interaction with mRNA target that codes for transcriptional factors involved in the development and differentiation of lymphoid blasts. The interaction between miRNA–mRNA target could promote the subexpression of tumor-suppressor genes, leading to the development, proliferation, and progression of leukemic cells. (B) SNPs located on the gene structure would give rise to unstable miRNAs that increase their degradation rate or whose sequence change prevents the miRNA–mRNA target interaction, promoting the overexpression of oncogenes and eventually the progression of leukemic cells.