New Insights into Acute Myeloid Leukemia: Pathogenesis, Treatment Challenges, and Promising Approaches
Acute myeloid leukemia (AML) is a malignant tumor that originates in the bone marrow, specifically from immature myeloid progenitor cells. This condition leads to an accumulation of dysfunctional blast cells and a deficiency of normal blood cells. AML is known for its significant molecular and genetic heterogeneity, making it challenging to classify and treat effectively.
Despite continuous updates in AML classification and emerging research on its pathophysiology, the first-line treatment for the majority of AML patients still involves a combination of cytarabine and an anthracycline. Although many patients achieve complete remission initially, a considerable number of them experience relapse and develop drug resistance over time.
Recent advancements have led to the approval of new drugs for specific AML subtypes. However, there remains a critical need for a deeper understanding of the disease’s pathogenesis, including better identification of genetic and epigenetic risk factors. This knowledge is crucial for developing more effective treatment regimens that can improve the overall outcomes for AML patients.
In a groundbreaking study (Study I), researchers investigated the off-target effects of a drug called APR-246, originally developed to restore the activity of a mutated TP53 protein. The study revealed that oxidative stress-related genes, including heme oxygenase-1 (HO-1), SLC7A11, and RIT1, were significantly upregulated in response to APR-246. Furthermore, they found that the upregulation of Nrf2, which induces the expression of HO-1, enhanced the cytotoxicity of APR-246. By using PI3K and mTOR inhibitors to prevent Nrf2 from translocating into the nucleus, researchers were able to enhance cell killing. This highlights the potential of combining APR-246 with PI3K and mTOR inhibitors to improve sensitivity to APR-246 and achieve better anti-leukemic effects.
In another study (Study II), scientists aimed to determine the viability of using stroma cells in diagnostic AML samples as a source of germline DNA. Obtaining germline DNA, along with DNA from leukemic cells, is crucial for accurately defining somatic mutations in AML cells. The researchers successfully cultivated and expanded bone marrow stroma cells from vitally frozen mononuclear cells taken from AML patients with monosomy 7. These cultivated stroma cells were stable and capable of differentiating into adipocytes or osteocytes after six weeks of culture. Importantly, the researchers found that the cultivated stroma cells did not carry the somatic mutations present in the malignant cells. This discovery suggests that bone marrow stroma cells from diagnostic bone marrow samples could serve as a reliable source of germline DNA for AML patients.
In Study III, the focus was on studying the binding occupancy of the chromatin organizer CTCF in AML patient cells, comparing it to its binding in normal CD34+ cells. The researchers discovered that AML cells displayed an abnormal increase in CTCF binding. Further analysis revealed that the gained CTCF sites were enriched with transcription factors such as PU.1, RUNX1, and CEBPA, which play significant roles in normal myeloid development. AML patients with TET2 mutations exhibited even more significant gains in CTCF occupancy, primarily annotated to promoters. These gained CTCF sites were associated with hypomethylated genes that were upregulated in AML. By performing knockdown experiments in K562 cells, the researchers found that the loss of CTCF resulted in decreased gene expression and the loss of RUNX1 binding at common CTCF and RUNX1 binding sites. Additionally, the knockdown of CTCF led to increased differentiation of K562 cells. In vitro exposure of AML patient cells to azacytidine caused significant changes in CTCF occupancy, with most gained sites exhibiting a binding pattern similar to that found in normal CD34+ cells. This study suggests that abnormal CTCF occupancy in AML may play a role in driving leukemogenic gene expression patterns.
Overall, these recent studies offer valuable new insights into the pathogenesis of AML, the challenges encountered in treating the disease, and promising approaches to improve outcomes. With a better understanding of genetic and epigenetic risk factors, researchers and clinicians can develop targeted treatment regimens that effectively combat drug resistance and enhance the overall survival rates for AML patients.
