Abstract
Leukemic cells originate from the malignant transformation of undifferentiated myeloid/lymphoid hematopoietic progenitors normally residing in bone marrow. As the precise molecular mechanisms underlying this heterogeneous disease are yet to be disclosed, the identification and the validation of novel actors in leukemia is of extreme importance. Here, we show that KCTD15, a member of the emerging class of KCTD ((K)potassium Channel Tetramerization Domain containing) proteins, is strongly upregulated in patients affected by B-cell type acute lymphoblastic leukemia (B-ALL) and in continuous cell lines (RS4;11, REH, TOM-1, SEM) derived from this form of childhood leukemia. Interestingly, KCTD15 downregulation induces apoptosis and cell death suggesting that it has a role in cellular homeostasis and proliferation. In addition, stimulation of normal lymphocytes with the pokeweed mitogen leads to increased KCTD15 levels in a fashion comparable to those observed in proliferating leukemic cells. In this way, the role of KCTD15 is likely not confined to the B-ALL pathological state and extends to activation and proliferation of normal lymphocytes. Collectively, data here presented indicate that KCTD15 is an important and hitherto unidentified player in childhood lymphoid leukemia, and its study could open a new scenario for the identification of altered and still unknown molecular pathways in leukemia.
Highlights
Leukemic cells originate from the malignant transformation of undifferentiated myeloid or lymphoid hematopoietic progenitors normally residing in bone marrow[1]
The search for novel key players in leukemia etiology and/or for novel biomarkers was here started through gene expression profiling using RNA-sequencing (RNA-seq) of leukemic cells purified from three pediatric patients affected by B-cell type acute lymphoblastic leukemia (B-Acute lymphoid leukemia (ALL)) (Table 1, patients a-c)
In order to confirm and extend the data emerged from the RNAseq analysis, we decided to evaluate the expression of the KCTD15 gene and of the encoded protein in a second set composed of 12 patients at diagnosis and at day + 33 after induction therapy when minimal residual disease was undetectable according to the clinical reports and bone marrow (BM) smear examination (Supplementary Fig. 1 for some exemplificative images)
Summary
Leukemic cells originate from the malignant transformation of undifferentiated myeloid or lymphoid hematopoietic progenitors normally residing in bone marrow[1]. It is important to consider the occurrence of additional aberrations that are able to contribute to leukemogenesis as in the case of deletions, amplifications, sequence mutations, and epigenetic lesions[5] In this intricate scenario, the identification of important players, at genetic and protein levels, may represent a valuable tool to gain insights into the mechanism underlying the etiology of the disease. On the basis of these considerations, we here started a search for novel leukemia biomarkers by comparing the RNA expression profiles of B-ALL patients with those of healthy subjects These analyses highlighted that mRNAs of the gene encoding the protein KCTD15, a member of the emerging protein class KCTD (potassium channel tetramerization domain)[11,12,13,14,15,16], is strongly upregulated in common B-ALL patients. Data here presented indicate that KCTD15 is an important and hitherto unidentified player in this kind of childhood leukemia
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