Inhibition of BCR::ABL1 tyrosine kinase activity Aids in the Generation of Stable Chronic Myeloid Leukemia Induced Pluripotent Stem Cells

Benjamin, E. S. B.; Babu, D.; Joshi, G.; Rajamani, B. M.; Nandy, K.; Rani, S.; Anandhan, S.; PremKumar, C.; Maddali, M.; Abraham, A.; Velayudhan, S. R.; Balasubramanian, P.

doi:10.1101/2023.06.01.543015

bioRxiv · 10.1101/2023.06.01.543015

Inhibition of BCR::ABL1 tyrosine kinase activity Aids in the Generation of Stable Chronic Myeloid Leukemia Induced Pluripotent Stem Cells

Benjamin, E. S. B.·Babu, D.·Joshi, G.·Rajamani, B. M.·Nandy, K.·Rani, S.·Anandhan, S.·PremKumar, C.·Maddali, M.·Abraham, A.·Velayudhan, S. R.·Balasubramanian, P.

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Abstract

Induced pluripotent stem cells (iPSCs) generated from patients with chronic myeloid leukemia (CML) have the potential for disease modeling to study disease pathogenesis and screening therapeutic interventions. In this study, we aimed to generate iPSCs from CD34+ hematopoietic progenitors of CML patients with varying responses to tyrosine kinase inhibitor (TKI) therapy. The generated CML-CD34-iPSC colonies displayed atypical "dome-shaped" morphology and underwent spontaneous differentiation in a few days. However, supplementation with imatinib (IM), the most widely used TKI to treat CML patients, in the culture medium improved the stability and maintenance of all isolated CML-CD34-iPSC colonies, allowing them to be maintained for more than 20 passages without significant differentiation. In contrast to previous studies, our results indicate that suppressing the BCR::ABL1 oncogenic pathway is essential for efficiently generating stable CML-iPSC colonies. Furthermore, we successfully differentiated these iPSCs to CD34+ hematopoietic progenitors both in the presence and absence of IM. This robust protocol for generating CML-iPSCs provides a valuable resource for disease modelling. The generated iPSCs will be a valuable tool for investigating CML pathophysiology, drug resistance mechanisms, and drug screening to identify novel and effective therapies for this disease.

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Benjamin, E. S. B., Babu, D., Joshi, G., Rajamani, B. M., Nandy, K., Rani, S., Anandhan, S., PremKumar, C., Maddali, M., Abraham, A., Velayudhan, S. R., Balasubramanian, P.. 2023-06-05. Inhibition of BCR::ABL1 tyrosine kinase activity Aids in the Generation of Stable Chronic Myeloid Leukemia Induced Pluripotent Stem Cells. https://doi.org/10.1101/2023.06.01.543015

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