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Bulk RNA-seq analysis of primary CML CD34+ cells (n=3) treated with idasanutlin alone or in combination with nilotinib in vitro

ABSTRACT: Bulk RNA-seq was performed on primary human CML CD34+ cells to understand the molecular consequences of treatment with the MDM2 inhibitor idasanutlin alone and in combination with the tyrosine kinase inhibitor nilotinib for 24 hrs and 72 hrs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218183 | GEO | 2023/12/19

REPOSITORIES: GEO

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Project description:The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor that strongly associates with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR-ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Microarray analysis of human CML- vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, further linking fibrosis to LSC persistence. Although we have not investigated whether MF is directly responsible for LSC persistence or whether it is merely an epiphenomenon occurring alongside the development of an LSC-supportive niche, we strongly believe that this is a mechanism that merits further investigation We used microarrays to compare MSCs expression profiles of HD vs. CML patients.

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Bulk RNA-seq analysis of primary CML CD34+ cells (n=3) treated with idasanutlin alone or in combination with nilotinib in vitro

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