28 June 2019

A stress-responsive protein plays an important role in the recurrence of chronic myeloid leukaemia (CML), a US study has found.

Researchers from the University of Alabama showed how SIRT1 helps to maintain the regenerative potential of CML leukaemic stem cells.

Writing in the Journal of Clinical Investigation, Dr Ajay Abraham and colleagues say that while CML patients can be treated with tyrosine kinase inhibitors effectively, primitive leukaemia stem cells are resistant to treatment, proving a major barrier to curing the disease.

As a result, the majority of patients with CML require indefinite inhibitor treatment to prevent disease recurrence.

Senior author Dr Ravi Bhatia said: “Our studies provide a conceptual advance and new biological insights regarding the activity of SIRT1 and its role in CML leukaemic stem cells.”

In 2012, Dr Bhatia and colleagues found that SIRT1 was overproduced in CML leukaemic stem cells compared with normal hematopoietic stem cells. SIRT1 contributed to leukaemic stem cell maintenance and resistance to tyrosine kinase inhibitors, but the mechanisms underlying this were not known.

In the current study, the team used a CML mouse model that also has a genetic deletion of Sirt1, which allowed them to compare wild-type leukaemic stem cells with SIRT1-deleted leukaemic stem cells.

To produce the energy they need, normal haematopoietic stem cells are dependent on a process known as glycolysis. However, leukaemia stem cells are more dependent on oxidative phosphorylation to produce energy. The scientists found that this increased reliance on oxidative phosphorylation does not depend on the BCR-ABL mutant protein which leads to CML, but is caused by a separate mechanism instead.

The researchers demonstrated that it is SIRT1 which plays a key role in enhancing oxidative phosphorylation in leukaemic stem cells.

The SIRT1 deletion in the mouse model impaired CML development, with significant delays in developing increased numbers of leukocytes and neutrophils, and delayed enlargement of the spleen and mortality. The deletion also reversed redistribution of CML stem cells from the bone marrow to the spleen.

SIRT1 is a deacetylase enzyme, and one of its targets is PGC-1α. The team showed that a drug which inhibits PGC-1α had a similar effect to the SIRT1 deletion, significantly reducing mitochondrial oxygen consumption, a sign of oxidative phosphorylation.

This discovery supports an important role for PGC-1α in the regulation of mitochondrial metabolism in CML stem cells.

Dr Bhatia says the impact of this study extends to other haematological malignancies, including acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms.

“Our research reveals new knowledge and concepts regarding the role of SIRT1 in metabolic regulation of hematopoietic stem cell and leukaemic stem cell maintenance, growth and resistance,” he said. “This raises the possibility of developing improved strategies to target kinase-independent metabolic alterations.”

Source: Abraham, A., Qiu, S., Chacko, B.K., Li, H., Paterson, A., He, J., Agarwal, P., Shah, M., Welner, R., Darley-Usmar, V.M., Bhatia, R. (2019) “SIRT1 regulates metabolism and leukemogenic potential in CML stem cells”, J Clin Invest, available from doi: 10.1172/JCI127080


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