Myeloid malignancies, including chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML), display upregulation of IL1RAP at the cell surface of the primitive (CD34+CD38-) leukemic cells (Järås et al. PNAS, 2010; Barreyro et al. Blood, 2012; Askmyr et al. Blood 2013). IL1RAP is an essential co-receptor for the interleukin-1 (IL1R1) and the interleukin-33-receptors (IL33R, ST2) to convey signals upon binding by their ligands IL1 and IL33, respectively. IL1RAP has previously mainly been studied in the context of inflammation and little is known about its role in normal hematopoiesis and if it’s upregulation in malignant hematopoiesis is of pathogenetic importance.

In this study, we first characterized normal hematopoiesis in Il1rap(-/- ) mice, and discovered that these mice displayed a reduction in myeloid cells in the peripheral blood (9.8x10^5 vs. 1.68x10^6 myeloid cells per mL, p=0.0076), suggesting that Il1rap is involved myelopoiesis. To test whether Il1rap regulates normal hematopoietic stem cells (HSC), we performed competitive stem cell transplantations, and demonstrated that Il1rap-/- HSC gave rise to equal donor contribution as Il1rap+/+ HSC, even in secondary transplantations, suggesting that Il1rap is dispensable for normal HSC function.

As IL1RAP is upregulated in myeloid neoplasms but it has been unclear whether this upregulation is functionally involved in disease biology, we next explored if IL1RAP upregulation alone is sufficient to cause features of a myeloid neoplasm. To this end, we retrovirally expressed IL1RAP along with GFP in cord blood (CB) CD34+ cells and transplanted the cells to NSG mice. At 200 days post transplantation, a striking myeloid lineage skewing (67% N=6, vs. 34% N=3, CD33+ among GFP+ cells in bone marrow, p=0.031), accompanied by a reduction of CD19+ cells (21% vs. 53%, p=0.041), was observed in mice that had received IL1RAP overexpressing (IL1RAP+) cells. In addition, mice that had received IL1RAP+ cells displayed enlarged spleens (102 mg vs. 71mg, p=0.034) and showed a myeloid cell expansion when compared to MIG control mice (10% vs. 3.7% CD33+ among GFP+ cells, p=0.035).

Having demonstrated that IL1RAP is involved in steady-state myelopoiesis and that IL1RAP upregulation leads to myeloid lineage skewing, we next investigated if primary CML primitive cells display a different sensitivity for cytokines (IL1B and IL33) that signal through IL1RAP-associated receptors. CB and CML cells were stimulated with either single cytokines or cytokines in combination with SCF, in serum free liquid cultures. Whereas IL1B did not affect the in vitro proliferation of normal CB CD34+ cells, primary CML CD34+ cells, and particularly CML CD34+CD38- cells, showed a strong response to IL1B stimulation with more than 10-fold higher cell counts compared to unstimulated CML CD34+CD38- cells, following 7 days of culture (5.6x103 vs. 7.5x104 cells p= 0.006), while IL33 had minor effects (5.6x103 vs. 8.5x103 p=0.040), suggesting that IL1RAP upregulation may render primitive malignant myeloid cells hypersensitive to IL1B stimulation.

In summary, these findings demonstrate that IL1RAP is involved in steady state myelopoiesis and that enforced IL1RAP expression, in cord blood CD34+ cells, alone is sufficient to induce features of a myeloproliferative disorder in mice. Primitive CML cells with upregulation of IL1RAP at the cell surface were more sensitive to IL1B compared to corresponding normal cells, which were unaffected. Collectively, these observations suggest that IL1RAP upregulation may contribute to the pathogenesis of myeloid neoplasms.


Richter:Cantargia: Consultancy, Equity Ownership. Järås:Cantargia: Equity Ownership. Fioretos:Cantargia AB: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.