Treating leukemia at the risk of inducing severe anemia

Abstract

Anemia is a frequently observed adverse effect in cancer patients who receive chemotherapy or drugs designed to block specific oncogenic signaling pathways, although the underlying mechanisms are poorly understood. An article first published online (Zhu HH, Luo X, Zhang K, et al. Proc Natl Acad Sci USA 2015;112:13342-13347) presented data indicating that cell type-specific pathway cross-talk is likely an important mechanism to consider. Shp2 and Pten, two master regulators of central cytoplasmic signaling pathways, oppose each other in myeloproliferation and leukemogenesis, but cooperate in promoting erythropoiesis. Thus, genetic ablation or pharmacologic inhibition of Shp2 suppresses the leukemogenic effect of Pten loss, yet simultaneously induces severe anemia in mice with Pten deficiency in blood cells.

Figure 1

Shp2 and Pten in leukemia and anemia. (A) Simplified hematopoietic lineage tree marked with the effects of targeted gene deletion. The red and green arrows indicate increases and decreases in the cell populations in Shp2 KO (SKO) and Pten KO (PKO), respectively. Ablation of Shp2 compromised the effect of Pten deletion in myelopoiesis. The blue arrow specifically denotes the combined effect of dual Shp2 and Pten knockout in DKO mice. The increase in BFU-E was followed by a dramatic decrease in CFU-E in DKO mice, which along with elevated reactive oxygen species, impaired survival, and other defects, eventually leads to severe anemia. (B) Pten deficiency promotes leukemia development and also causes mild anemia. Shp2 inhibitor can suppress the leukemogenic effect of Pten loss, but may trigger severe anemia in the background of Pten deficiency. This calls for caution and genetic screening for Pten mutations or deficiency in cancer patients before prescription of pharmaceuticals designed to suppress the Ras–Erk pathway. BFU-E = Erythroid burst-forming units; CFU-E = erythroid colony-forming units; MPP = multipotent progenitors; CMP = common myeloid progenitors; CLP = common lymphoid progenitors; MEP = megakaryocyte/erythrocyte progenitors; GMP = granulocyte/macrophage progenitors; Pro-L = prolymphocytes; Lym = lymphocytes; RBC = red blood cells.