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Bone marrow CD34+/lin- cells of patients with Chronic Phase- Chronic Myeloid Leukemia (CP-CML) after 12 months of nilotinib treatment exhibit a different expression signature compared to the diagnosis and the same cells from healthy subjects

ABSTRACT: Chronic Phase-Chronic Myeloid Leukemia (CP-CML) is defined by the presence of BCR-ABL1 fusione gene, which encodes a tyrosine kinase protein that drives the uncontrolled proliferation and survival of leukemic stem cells (LSCs). Nilotinib, a tyrosine kinase inhibitor, targets the activity of BCR-ABL1 by reducing aberrant signalling pathways which drive the regeneration of LSCs. Despite nilotinib’s action, a population of resilient LSCs persist in the bone marrow (BM) and can indeed drives relapse and progression in CML patients. Our study investigated the gene expression profiling (GEP) of BM CD34+/lin- cells from 79 CP-CML patients at diagnosis compared to the BM CD34+/lin- cells from the same patients after 12 months of nilotinib treatment, and to the normal cell counterpart from 10 donors (CTRLs). GEP analyses identified 3012 significantly differentially expressed genes. Among these, we focused on certain genes involved in crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. We demonstrated the upregulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs. We highlighted that certain transcriptome features characterizing the diagnosis persist after 12 months of nilotinib treatment compared to CTRLs, potentially influencing the self-renewal and survival properties of LSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279135 | GEO | 2025/04/02

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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Bone marrow CD34+/lin- cells of patients with Chronic Phase- Chronic Myeloid Leukemia (CP-CML) after 12 months of nilotinib treatment exhibit a different expression signature compared to the diagnosis and the same cells from healthy subjects

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