ASH2020 | Dr. Diletta Fontana: Obtain more insights into the molecular mechanisms governing aCML development and progression is important
Q1: Atypical Chronic Myeloid Leukemia(aCML) is a kind of hematological malignancies without Ph chromosome and Bcr-abl fusion gene. Firstly, could you talk about the incidence and treatment status of aCML?
aCML is a rare MDS/MPN neoplasm which affects elderly patients with a median age ranging between 60 and 76 years, and with an apparent male predominance. Its estimated incidence is 1 case for every 100 cases of t(9;22) BCR/ABL1-positive chronic myeloid leukemia, meaning 1 case per 1000000 persons per year or less.
No established standards of care exist for the treatment of aCML. Moreover, no consensus recommendations such as risk-based treatments algorithms exist to help clinicians in choosing between a watch-and-wait approach and initiation of therapy.
During the last years, different therapeutic approaches were used, but at present, allogeneic hematopoietic stem cell transplantation remains the only curative treatment option. However, it should be considered only for young eligible patients with a suitable donor, since the elderly age of patients makes the transplant outcome difficult. In older patients, especially with lower-risk disease, monitoring or palliative chemotherapy may be appropriate.
Regarding other medical therapies, hydroxyurea is used as a supportive care measure to control hyperleukocytosis or splenomegaly. Moreover, complete and partial hematological remissions have been reported also after treatment with interferon alfa. However, both hydroxyurea and interferon alfa, despite being able to improve the white blood cell count, are unable to change the course of the disease.
Q2：ETNK1 mutation is vital to aCML patients, so could you explain how ETNK1 mutation influences the development or treatment of aCML ?
ETNK1 mutations induce a reduction in the phosphoethanolamine intracellular level, which in turn negatively modulates complex II activity, leading to an increased mitochondrial activity and ROS production. Since ETNK1 mutations are an early event in the clonal evolution history of aCML, they are mainly responsible for the induction of a mutator phenotype, which, in turn, can promote the development of new mutations and chromosomal instability, therefore accelerating the process of clonal evolution.
Q3: at ASH 2020 meeting, fundamental research of your team shows that ETNK1 mutations in aCML induce a mutator phenotype that can be reverted with phosphoethanolamine. As the leading author, could you interpret this study?And will it bring improvement to therapy of aCML?
We suggest a new mechanism by which the impairment of ETNK1 function and the consequent reduction in the P-Et content cause an increase in mitochondrial activity due to a reduced competition between P-Et and succinate for complex II. This increased mitochondrial activity is responsible for the enhanced ROS production, which leads to accumulation of DNA mutations. These findings are interesting as the parallel analysis of aCML subclonal architecture indicates ETNK1 mutations as a very early event in the history of the disease. This suggests that ETNK1 mutations could contribute to the onset of aCML through the activation of a mutant phenotype, which in turn would accelerate the accumulation of further oncogenic mutations. Furthermore, the ability of P-Et to restore the basal mitochondrial activity, as well as ROS level, besides slow down the accumulation of further mutations, at least in vitro, suggests possible future therapeutic options for the treatment of patients affected by aCML ETNK1-positive.
Our findings are relevant if we consider that to date there are no standards of care for the treatment of aCML. However, it is fitting to highlight that P-Et is not able to eradicate ETNK1+ clone. However, considering that ETNK1 mutations are an early event in the clonal evolution history of aCML, P-Et treatment can prevent the accumulation of further mutations, and therefore the clonal expansion of the disease.
Q4：based on current research, which direction deserves to be explored in your opinion? is there any progress that has been made?
In my opinion, regarding the possible treatment with phosphoethanolamine, the effect and the efficacy in vivo have to be tested.
Considering aCML, it will be important to obtain more insights into the molecular mechanisms governing aCML development and progression, and to convert them into better treatment strategy modalities, since no effective therapies are available to date for aCML and the outcome is almost invariably fatal.