HomeENGLISH MAGAZINEEnveloping leukemia: from genetic variants to "fiery" cytokines, no rest 'til the...

Enveloping leukemia: from genetic variants to “fiery” cytokines, no rest ‘til the enemy is sent to the depths

Cancers can grow when tumor cells are not identified or destroyed by the immune system. Autoimmune diseases, on the contrary, occur when the immune system attacks our own cells, mistaking them for foreign cells. According to a new study from the Garvan Institute of Medical Research, some gene variants associated with leukemia can produce ‘rogue’ immune cells that drive autoimmune diseases, explaining their incidence in the context of these blood cancers. Scientists had previously noticed that leukemia patients were also likely to develop an autoimmune disease, such as rheumatoid arthritis or aplastic anemia. Research into this link revealed that immune cells called natural killer (NK) cells – responsible for destroying pathogens and harmful or infected cells – were a key player. This new research provides insight into the role these killer T cells play in leukemia and autoimmune disease. Scientists found that gene variations affecting a protein that controls the growth of killer T cells can turn them rogue.

They employed a new high-resolution screening methods to look at blood from children with rare inherited autoimmune diseases. They then used the CRISPR/Cas9 technique, a genome editing tool, to find out what happens when the protein STAT3 is genetically altered. STAT3 is a transcription factor found in every cell and is critical for various cell functions, like bone marrow stem cells regeneration, cytokine production and control over the commitment of the immune system’s B and T lymphocytes. STAT3 is also malfunctioning in leukemias, bone marrow failure (myelodysplasia) and is over-espressed in some types of human cancers. The team found that if these proteins are altered, they can cause rogue killer T cells to grow unchecked, resulting in enlarged cells that bypass immune checkpoints to attack the body’s own cells. In addition, even just 1-2% of a person’s T cells going rogue could cause autoimmune disease.

The team’s research may help develop screening technologies that clinicians could use to sequence the complete genome of every cell in a blood sample, to identify which cells might turn rogue and cause disease. Future applications could include better targeting of medication, like available JAK inhibitors (e.g. Ruxolitinib), based on the presence of these mutations. In conclusion, investigators showed that these rogue cells are driving the autoimmunity: they’re probably one of the cell types most directly contributing to it. It’s never been clear what the connection between leukemia and autoimmune disease is – whether the altered STAT3 protein is driving disease, or whether leukemic cells are dividing and acquiring this mutation just as a by-product. Further study is needed to determine what proportion of people with rheumatoid arthritis, systemic lupus and other autoimmune conditions have rogue cells and STAT3 variations.

In anothe recent study, instead, has investigated the involvement of cytokine and growth factor signaling in childhood forms of leukemia. Pediatric acute myeloid leukemia (pAML) is a heterogeneous disease with various subtypes based on genetic, transcriptional and epigenomic factors. Pro-inflammatory cytokine signaling pathways such as those of interleukin (IL)-6 are linked to various cancers, with IL-6 and IL-3 in synergy increasing hematopoietic stem cell proliferation. Poor outcomes of adult and pediatric AML are associated with high levels of IL-6 in the bone marrow. In adult AML, IL-6 also upregulates the STAT signaling pathway in stem cells and blood cell progenitors. JAK/STAT pathway inhibitors or anti-IL6 antibodies have shown promise in adult AML cases. In this new investigation, the researchers collected bone marrow samples from approximately 1500 patients diagnosed with pAML enrolled in the Children’s Oncology Group.

The researchers then conducted gene set enrichment analyses that were verified using previously published bone marrow RNA sequence data from an independent cohort. The immunological, genetic, demographic and transcriptomic profiles of patients expressing high levels of IL-6 and IL-6 receptors were also analyzed. Bone marrow cells from pAML patients expressing high levels of IL-6 and IL-6 receptors were cultured in human bone marrow stromal cells (HS-5 cells), which replicate the patterns of bone marrow stromal cell expression such as secretion of IL-6, IL-1β, c-KIT receptor and macrophage/granulocyte colony-stimulating factors M-CSF, G-CSF and GM-CSF. The results reported that more than 20% of pAML patients had high levels of IL-6 and higher inflammatory cytokine signaling activity, such as TNF-α, IFNα and IFNβ, and IL-1. These high levels of inflammatory cytokines and signaling activity were also associated with poor outcomes, such as a lower probability of event-free and overall survival for two years.

Cytometric CyTOF analysis indicated that distinct genomic subtypes of pAML having high IL-6 and IL-6 receptor levels have common pathways of receptor-mediated inflammatory signaling. Targeted sequencing identified five recurrent regions of somatic mutations, including various translocations and rearrangements that activated common STAT-mediated signal transduction and PI3K signaling pathways. The genomic subtypes associated with these somatic mutations also showed activation of NF-κB transcription factor which, along with STAT-3 is essential to the expression of protective cellular proteins like the anti-apoptotic Bcl-2. Irrespective of the genomic subtype, high IL-6/IL-6R levels were seen to be associated with the activation of the JAK/STAT, PI3K, NF-κBand ERK1/2 mitogenic kinases, In agreement, the in vitro, inhibition of JAK1/2 by Ruxolitinub was shown to downregulate receptor-mediated signaling by inflammatory cytokines.

Scientists deem thatt herapies comprising inhibitors of these co-activated pathways might benefit pAML patients with high circulating IL-6, by reducing the inflammatory cytokine signaling pathways across genetic subtypes. It would be like adopting a “sub-targetetd therapy” inside targeted therapy itself.

  • Edited by Dr. Gianfranceso Cormaci, PhD; specialist in Clinical Biochemistry.

Advised in this website

Extensive genome mapping for leukemia: a “must” effort to treat those “bloody” childhood forms (20/09/2022)

Sick to the bone: how a growth factor leads the marrow to drying up its normal stems (24/05/2021)

Metabokilling resistant leukemia: the old avenue with its alleys has not be forgotten after all (30/12/2020)

Leukemia field: rearranging and targeting are in both sides of the coin (13/12/2019)

Scientific references

Masle-Farquhar E et al. Immunity 2022 Nov 26, in press.

Bolouri H et al. Nature Commun 2022 Nov 23; 13(1):7186.

Masle-Farquhar E et al. Cell Rep. 2022; 38(3):110259.

Bolouri H et al. PLoS One. 2021 Nov; 16(11):e0259197.

Singh M, Jackson KJL et al. Cell. 2020; 180(5):878-894.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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