Patients with acute myeloid leukemia can be subclassified based on the constitutive cytokine release of the leukemic cells; the possible clinical relevance and the importance of cellular iron metabolism

ABSTRACT

Objective: Acute myeloid leukaemia (AML) is a heterogeneous malignancy; we studied how the constitutive cytokine release by the AML cells varies among patients.

Methods: We investigated the constitutive release of 28 mediators during in vitro culture for 79 consecutive patients.

Results: Constitutive cytokine release profiles differed among patients, and hierarchical clustering identified three subsets with high, intermediate and low release, respectively. The high-release subset showed high levels of most mediators, usually monocytic differentiation as well as altered mRNA expression of proteins involved in intracellular iron homeostasis and molecular trafficking; this subset also included 4 out of 6 patients with inv(16). Spontaneous in vitro apoptosis did not differ among the subsets. For the high-release patients, cytokines were released both by CD34⁺ and CD34⁻ cells. The mRNA and released protein levels showed statistically significant correlations only for eleven of the cytokines. The overall survival after intensive anti-leukemic therapy was significantly higher for high-release compared with low-release patients. Pharmacological targeting of iron metabolism (iron chelation, transferrin receptor blocking) altered the cytokine release profile.

Conclusions: Subclassification of AML patients based on the constitutive cytokine release may be clinically relevant and a part of a low-risk (i.e. chemosensitive) AML cell phenotype.

KEYWORDS:

• Acute myeloid leukemia
• cytokines
• differentiation
• Flt3 mutations
• iron metabolism

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

The study received financial support from the Norwegian Cancer Society [grant numbers 62370, 62371, and 100933], Helse-Vest [grant number 911788] and the University of Bergen.