Chronic immune stimulation of autoimmunity can trigger leukemia

There is accumulating evidence that autoimmunity must be considered in the case management for leukemia (AML and CLL) not only in regard to complications but as a causative factor. A paper published recently in the journal Haematologica addresses this concern:

"There is considerable evidence to suggest that there is an increased occurrence of hematologic malignancies in patients with autoimmune diseases compared to the general population, with a further increase in risk after exposure to cytotoxic therapies...an increased awareness of this risk and further investigation into the pathogenetic mechanisms of acute leukemia in autoimmune disease patients are warranted."

They argue against labeling leukemias that develop in patients with autoimmune diseases who are exposed to cytotoxic agents as ‘therapy-related leukemias’, and review the literature that demonstrates the association of leukemia with autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis. They point out the obvious when they state:

"Tumor cells need to evade the immune system to develop overt disease, thus defects in the immune system are recognized risk factors for cancer development. In turn, patients diagnosed with diseases involving a defective immune system, or those receiving immunosuppressive therapies, are believed to be at high risk of developing acute leukemia."

Practitioners and frequent readers here will be familiar with the importance of NF-kappaB (nuclear factor kappa beta) and inflammatory cytokines in autoimmune diseases...

"Both specific and non-specific immune responses play a major role in controlling the growth of malignant cells (tumor surveillance). Any disruption of this system by a primary pathological or iatrogenic process will provide the opportunity for abnormal cells to evade surveillance and progress into malignancy. In addition, the interaction between tumor cells and the host microenvironment of stromal cells and inflammatory/immune cells contributes to a complex inflammatory signaling process that enhances tumor progression. For example, NF-kappaB a major player in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, is involved in cancer and leukemia development. Furthermore, chemokines and cytokines produced by inflammatory cells have a powerful pro-tumor activity. Early in the neoplastic process, inflammatory cells facilitate genomic instability, promote angiogenesis and create an attractive environment for tumor growth."

In their conclusion the authors assert:

"Our focus should be on investigating the molecular defects in the autoimmune diseases, including defects in immunity, DNA repair, and apoptosis in these patients rather than studying only drug mechanisms that lead to leukemogenesis. ...Finally, the risk of AML in AD patients warrants more attention, as it provides a model for investigating the role of defective immunological mechanisms in leukemogenesis."

A study investigating chronic immune stimulation as a trigger for leukemia published in the Journal of Clinical Oncology is also of interest. In this case the authors pay special attention to the role of infections (which we know can trigger autoimmune disorders):

"Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections...To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases."

They calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for the association of AML or MDS with infectious and/or autoimmune diseases for 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls and found a strong association:

"Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS."

The associations of autoimmune disease with acute myeloid leukemia and myelodysplastic syndrome were particularly strong. The authors conclude:

"Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions."

Note that the authors of the first paper presented above caution against attributing causation to a treatment effect.The authors of a paper published in  the Journal of Czech Physicians (Časopis lékařů českých) include chronic lymphocytic leukemia (CLL) in their comments:

"Evidence has been growing that the pathogenesis of lymphoproliferative disease involves immune processes deregulation. It is believed that antigens or immunological elements can trigger transformation of normal lymphocyte polyclonal population into monoclonal neoplastic disorder – lymphoproliferative disease. Extensive studies point to the link between malignant lymphoma development and autoimmune or inflammatory diseases – namely rheumatoid arthritis, Sjörgen’s syndrome, coeliac disease, systemic lupus erythematosus or thyroiditis."

They state further...

"Besides various lymphomas, the links to autoimmune/inflammatory diseases have also been described in chronic lymphocytic leukaemia."

Clinicians should note:

"Regarding clinical medicine, it is necessary to distinguish patients with autoimmune, inflammatory and infectious diseases who are at the increased risk of tumour development. New approaches must be found to lower this risk."

A paper published recently in Current Opinion in Oncology considers chronic lymphocytic leukemia in particular. The authors observe:

"Autoimmune disorders can complicate CLL at any stage and even occur in the preleukemic monoclonal B lymphocytosis. CLL cells can act as antigen-presenting cells, possibly inducing the formation of autoreactive T helper cells (through the production of B-cell activator factor and a proliferation-inducing ligand) and nonfunctional T regulatory cells (via CD27–CD70 interaction). Further, nonmalignant lymphocytes may stimulate via CD154-mediated mechanism both tumor growth and the development of autoimmunity, especially after fludarabine-based regimens of therapy. CLL cells tend to produce monoclonal polyreactive autoantibodies suggesting that autoantigen stimulation via B-cell receptor signaling may affect the natural history of CLL...the pathogenetic intertwining between autoimmunity and malignant transformation indicates the importance of defining whether the occurrence of autoimmunity in CLL might be considered an autonomous prognostic indicator that influences treatment decisions."

Thus autoimmunity and the development and progression of chronic lymphocytic leukemia can be a two-way street. The authors summarize their findings:

"Simple-refractory and complex autoimmunity are independent indicators of therapy for CLL. Further, epidemiological and biological studies will help clarifying the prognostic and possibly also the pathogenetic significance of simple autoimmunity."

An interesting paper fresh of the presses in blood (Journal of the American Society of Hematology) examines one of the mechanisms by which autoimmunity may promote chronic lymphocytic leukemia (CLL):

"A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes."

In other words, PTPN22 suppresses the signals that are supposed to turn off lymphocytes that attack self-tissue. The authors make the fascinating observation:

"We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells."

So PTPN22 seems to play a significant role in autoimmunity and the immune dysregulation of chronic lymphocytic leukemia. Of interest from the therapeutic perspective:

"Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli."

If the authors' conclusion gains wide circulation then perhaps other more benign agents that downregulate PTPN22 may be found:

"Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors."

Lastly for this post, a paper published in Clinical Lymphoma Myeloma & Leukemia recognizes an association of non-hematologic autoimmune disorders with chronic lymphocytic leukemia.

"Autoimmune phenomena are well known to complicate chronic lymphocytic leukemia (CLL) and occur in 10% to 25% of patients. Hematologic autoimmune complications, particularly autoimmune hemolytic anemia and immune thrombocytopenia, are much more common than nonhematologic complications."

Not surprising since there is so much action going on in the blood compartment. But...

"We present 6 cases of patients who exhibited uncommon complications of CLL: myasthenia gravis, acquired von Willebrand disease, bullous pemphigoid, and acquired angioedema."

Importantly...

"In our patients, the activity and recrudescences of these complications were highly associated with CLL remission or progression. More awareness of the association of CLL with these complications could facilitate earlier diagnosis and effective treatment."

'Take home' message: the astute clinician should be aware of autoimmunity as both a possible causative and complicating factor in lymphoproliferative disorders such as leukemia (AML and CLL), lymphoma and myelodysplastic syndrome.