Case Study Presents 3 Potential Novel Targets in Acute Myeloid Leukemia

Patients with acute myeloid leukemia (AML) currently face a poor prognosis and complicated disease classification due to the disease’s complex genetic makeup. Targeting AML cells is difficult despite advances in the understanding of its genetic alterations, so a recent study aimed to add potential novel therapeutic targets and gene variants based on RNA sequencing.

AML is a hematological malignancy with a complicated genetic landscape, and previous studies have conducted large-scale genetic sequencing to further understand it. One study stratified AML’s genetic alterations into 4 main categories: coding region changes, splice variants, genomic regulatory regions, and non-repetitive sequences.

That study reported several known genetic fusions that initiate AML, including MLL, PML-RARA, and RUNX1-RUNX1T1 fusions. FLT3 and NPM1 gene mutations, among others, were also identified. SMC1A and AMC3 mutations were also reported, but less frequently. Novel fusions were also identified in 1 patient with AML, further suggesting that the disease has a complicated makeup inhibiting more effective targeting and more positive outcomes.

The current case study, published in Heliyon, explored the case of a 37-year-old woman diagnosed with AML after presenting with pancytopenia in the hospital following 2 weeks of general weakness and bone pain. The patient received induction chemotherapy with daunorubicin and cytarabine and achieved remission, was treated with allogeneic bone marrow transplantation, but died 7 months after initial diagnosis.

RNA sequencing of the patient’s sample showed a significant number of genes upregulated (2539) versus downregulated (252) compared with the control genetic profile—a difference study authors described as “remarkable.” Overall, they determined, “the difference between gene expression in the AML case patient and control was statistically significant.”

The top 8% of upregulated genes shown in RNA sequencing included ADAMTS14, ARHGAP22, and EPDR1, which was also reflected in real-time quantitative polymerase chain reaction (qPCR) results. All 3 genes were explored further using data from 200 AML patients in The Cancer Genome Atlas.

Single nucleotide polymorphism (SNP) and insertion/deletion (INDEL) analyses were performed to identify variants, and 4 were novel INDEL variants as well as 1 novel exonic SNP were identified in ADAMTS14. Studies in other cancer types have also highlighted ADAMTS14 as a potential player in disease progression, which authors of the current study suggest as a potential novel target in AML.

ARHGAP22 is also a potential target, study authors conclude. Novel INDEL and SNP variants were identified, and ARHGAP22 and other genes in its family of proteins may play roles in other cancer types such as melanoma and chronic lymphocytic leukemia.

EPDR1 is the final suggested novel target in this study, and it is another candidate that has shown relevance in the proliferation of other cancer types, including colorectal cancer and hepatocellular carcinoma.

ADAMTS14, ARHGAP22, and EPDR1 expression was not significantly different in survivors versus deceased patients in the study, suggesting they may not be associated with overall survival outcomes.

Larger studies are needed to confirm the association of this trio of upregulated genes with AML, but they offer potential novel targets in AML, which is considered the most heterogenous form of hematological cancer.

“The present study showed the remarkable overexpression of the 3 genes in comparison to healthy control at the time of diagnosis,” study authors concluded, “which urges further investigation of their implications in disease initiation and perhaps potential use as biomarkers.”

Reference

El-Masry OS, Alamri AM, Alzahrani F, Alsamman K. ADAMTS14, ARHGAP22, and EPDR1 as potential novel targets in acute myeloid leukaemia. Heliyon. Published online March 6, 2022. doi:10.1016/j.heliyon.2022.e09065