Inflammation accelerates BCR-ABL1+ B-ALL development through upregulation of AID

Abstract

Inflammation contributes to the initiation and disease progression of several lymphoid malignancies. BCR-ABL1-positive B-cell acute lymphoblastic leukemia (BCR-ABL1+ B-ALL) is triggered by the malignant cloning of immature B cells promoted by the BCR-ABL1 fusion gene. However, it is unclear whether the mechanism driving the disease progression of BCR-ABL1+ B-ALL involves inflammatory stimulation. Here, we evaluate BCR-ABL1+ B-ALL cells’ response to inflammatory stimuli lipopolysaccharide (LPS) in vitro and in vivo. The results indicate that LPS promotes cell growth and genomic instability in cultured BCR-ABL1+ B-ALL cells and accelerates the BCR-ABL1+ B-ALL development in a mouse model. We show that the LPS-induced upregulation of activation-induced deaminase (AID) is required for the cell growth and disease progression of BCR-ABL1+ B-ALL. Moreover, AID modulates the expression of various genes that are dominated by suppressing apoptosis genes and upregulating DNA damage-repair genes. These genes lead to facilitation for BCR-ABL1+ B-ALL progression. The heat shock protein 90 (Hsp90) inhibitors significantly reduce AID protein level and delay the disease progression of BCR-ABL1+ B-ALL upon inflammatory stimulation. The present data demonstrate the causative role of AID in the development and progression of BCR-ABL1+ B-ALL during inflammation, thus highlighting potential therapeutic targets.

Inflammation as a driver of hematological malignancies

“…AID expression has been associated with blast crisis progression in CML and increases leukemogenesis in BCR-ABL + B-ALL ( 133 ). It has been recently investigated that inflammation contributes enhanced expression AID through NFκB pathway and further increases malignancy in BCR-ABL + B-ALL ( 134 ). BCR-ABL tyrosine kinase inhibitors like imatinib mesylate was the first drug approved for CML.…”

Prognostic Impact of Copy Number Alterations’ Profile and AID/RAG Signatures in Acute Lymphoblastic Leukemia (ALL) with BCR::ABL and without Recurrent Genetic Aberrations (NEG ALL) Treated with Intensive Chemotherapy

“…Interestingly, in contrast to RAG2, AID was found to be also upregulated by environmental factors, like repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood [13,22,25,27]. Recent studies also describe a depleted microbiome as an accelerator of ALL development, while metabolites of a healthy microbiome prevented leukemia through AID inhibition [58][59][60].…”

“…AID was documented to be a driver of oncogenic mutations in lymphomas [23,24]. However, recent studies have shown that aberrant activation of AID by infectious signals may also accelerate mutagenic processes leading to childhood ALL [13,[25][26][27]. The abovepresented mutational mechanisms have been well described in pediatric ALL, but the data are insufficient for adult ALL.…”

T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including Hepatocyte Growth factor

“…Cytokines are essential for BM niche homeostasis, and the first studies on B-ALL reported a higher expression of these molecules when compared with healthy BM samples, suggesting an autocrine/paracrine regulation of leukemic cells and cytokines 22 . More recently, studies have demonstrated that inflammation can drive progression of BCR-ABL1 B-ALL 23 . The composition and the contribution of the inflammatory microenvironment in T-ALL still remains poorly explored.…”