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. 2025 Mar 18;17(6):1022.
doi: 10.3390/cancers17061022.

Bone Marrow CD34+/lin- Cells of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) After 12 Months of Nilotinib Treatment Exhibit a Different Gene Expression Signature Compared to the Diagnosis and the Corresponding Cells from Healthy Subjects

Alessandra Trojani  1 , Ester Pungolino  1 , Barbara Di Camillo  2 , Luca Emanuele Bossi  1 , Cassandra Palumbo  1 , Mariella D'adda  3 , Alessandra Perego  4 , Mauro Turrini  5 , Chiara Elena  6 , Lorenza Maria Borin  4 , Alessandra Iurlo  7 , Simona Malato  8 , Francesco Spina  1 , Maria Luisa Latargia  9 , Pierangelo Spedini  10 , Salvatore Artale  11 , Michela Anghilieri  12 , Maria Cristina Carraro  13 , Cristina Bucelli  7 , Alessandro Beghini  14 , Roberto Cairoli  1
Affiliations

Bone Marrow CD34+/lin- Cells of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) After 12 Months of Nilotinib Treatment Exhibit a Different Gene Expression Signature Compared to the Diagnosis and the Corresponding Cells from Healthy Subjects

Alessandra Trojani et al. Cancers (Basel). .

Abstract

Background: Chronic-Phase Chronic Myeloid Leukemia (C-PCML) is defined by the presence of the BCR-ABL1 fusion 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 signaling 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 drive relapse and progression in CML patients.

Methods: 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 counterpart cells from 10 donors (CTRLs).

Results: GEP analyses identified 3012 significantly differentially expressed genes across these comparisons. Among these, we focused on certain key genes associated with eight crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. Within these pathways, we observed the up-regulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs.

Conclusions: We observed that certain transcriptome features present at diagnosis persisted after 12 months of nilotinib treatment, compared to CTRLs. This suggests that nilotinib may exert selective pressure, potentially supporting the survival and self-renewal of LSCs. Future insights into these pathways could help identify therapeutic targets to improve outcomes in CML.

Keywords: Chronic-Phase Chronic Myeloid Leukemia (C-PCML); KEGG pathways; bone marrow CD34+/lin− cells; differentially expressed genes (DEGs); gene expression profiling (GEP).

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of the data, in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Heatmaps of Chronic Myeloid Leukemia. Heatmaps depicting the RMA-normalized expression levels (log2 scale) of DEGs in Chronic Myeloid Leukemia at month 0, after 12 months of nilotinib, and in CTRL subjects. Hierarchical clustering using average linkage was applied to the genes to enhance visualization.
Figure 2
Figure 2
Heatmaps of JAK-STAT signaling pathway. Heatmaps depicting the RMA-normalized expression levels (log2 scale) of DEGs in the JAK-STAT signaling pathway at month 0, after 12 months of nilotinib, and in CTRL subjects. Hierarchical clustering using average linkage was applied to the genes to enhance visualization.
Figure 3
Figure 3
Heatmaps of NF-kB signaling pathway. Heatmaps depicting the RMA-normalized expression levels (log2 scale) of DEGs in the NF-kB signaling pathway at month 0, after 12 months of nilotinib, and in CTRL subjects. Hierarchical clustering using average linkage was applied to the genes to enhance visualization.
Figure 4
Figure 4
Heatmaps of ABC transporters. Heatmaps depicting the RMA-normalized expression levels (log2 scale) of DEGs in the ABC transporters at month 0, after 12 months of nilotinib, and in CTRL subjects. Hierarchical clustering using average linkage was applied to the genes to enhance visualization.
See this image and copyright information in PMC

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