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Single cell analysis provides insight into primary resistance

Using single cell analysis, researchers have revealed cell populations that can predict primary resistance to imatinib in chronic myeloid leukaemia.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is a hematopoietic stem cell disease. It is caused by a single translocation event – t(9;22)(q34;q11) – which generates the fusion protein BCR-ABL. CML is responsive to treatment with targeted tyrosine kinase inhibitors (TKI). TKIs, such as imatinib and dasatinib, bind selectively to the active site of BCR-ABL. Nonetheless, some patients fail to benefit from TKI therapy and 3-5% of patients progress into blast crisis after treatment. Researchers have identified some underlying mechanisms for resistance to TKI treatment, including mutations in the fusion protein and trisomy.

Immune function in CML is also impaired. However, researchers have yet to sufficiently characterise the population structure of the peripheral blood within CML patients. Interestingly, researchers have previously observed an immune-modulatory role for TKI treatment. Yet, the specific changes in the expression programs remain unknown.

Single cell analysis

In a study, published in Aging, researchers performed single cell RNA-sequencing on a total of 41,723 cells from patients’ peripheral blood. These cells covered different TKI treatment stages of four CML patients to generate expression profiles for individual cells. They also analysed this data in association with expression profiles of 17,540 bone marrow cells from both CML patients and healthy donors to create a comprehensive landscape for CML.

Despite the small number of cases, the team were able to identify features of leukaemic cells that were common among patients. They were also able to discriminate between poor and favourable prognosis. Their analysis demonstrated that imatinib treatment significantly altered leukocyte population compositions in both responders and non-responders. It also affected the expression profiles of multiple cell populations, including non-neoplastic cell types. Notably, they found that in imatinib poor-responders, patient-specific pre-treatment unique progenitor cells were enriched in peripheral blood compared to responders.

These results indicate that resistance to TKIs might be intrinsic in some CML patients rather than acquired. It also suggests that non-neoplastic immune cell types may play a key role in dispersing the responsiveness of patients to TKIs. Most importantly, these results support the potential clinical utility of peripheral blood as a diagnostic tool in the TKI sensitivity of CML patients.

Image credit: By kjpargeter –

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Cancer / Cancer Research / Single cell