A possible cause for chemoresistance in leukemia: liquid tumors behaving as solid tumors. When a person with leukemia goes into remission, their cancer is under control—but only rarely is it eradicated. Leukemic tumors are often referred to as liquid tumors since they originate in the blood and bone marrow and can’t be excised like solid tumors. This makes it difficult, if not impossible, to get rid of all the cancer cells. Those that remain after treatment may have developed resistance to chemotherapy (i.e., chemoresistance).
Scientists have discovered that leukemia cells form solid tumors outside of the blood and bone marrow (termed extramedullary). Cells from these tumors may undergo changes that lead to chemoresistance, metastasize to the bone marrow, and cause it to be resistant to anti-leukemic agents. Not much is known about the behavior of these tumors, let alone how they contribute to treatment failure.
Cunningham et al. (2019) undertook a bedside-to-bench pilot study in which they used leukemic breast tumors to “study the natural history of leukemic tumors in a single organ.” What they found surprised them: the leukemic tumors were behaving like solid tumors.
Cunningham and colleagues used the Ion AmpliSeq Transcriptome Human GeneExpression Kit — a single-tube, targeted NGS assay—to profile more than 20,000 RefSeq genes using degraded RNA from formalin-fixed, paraffin-embedded (FFPE) breast tumor samples. They identified striking similarities in the gene expression profiles of leukemic breast tumors and solid breast tumors.
This, along with other clinical similarities in the growth of leukemic and solid tumors in breast, suggests that leukemic breast tumors may form through the interaction of the cells with an aberrant microenvironment as described in Paget’s 1889 “seed-and-soil” hypothesis, which says that cancer cells will only form tumors at sites where the local microenvironment is favorable, just like a seed will only grow in fertile soil .
Due to changes in an extramedullary tumor caused by interactions with its microenvironment, anti-leukemia agents designed to kill circulating leukemic cells may be rendered ineffective against it, and it can be said that the cells have acquired chemoresistance. According to the authors, “the failure of anti-leukemia agents to eradicate leukemic tumors that grow and spread while the drugs kill circulating leukemic cells points to the likelihood that supportive organ soil is unaffected by these agents.”
The authors point out that viewing leukemia as only a liquid cancer in every patient risks overlooking the potential that, in some patients, leukemic cells (or seeds) may settle on what Paget called an organ’s congenial soil and acquire solid tumor behavior that can affect treatment. The pilot study conducted by Cunningham et al. challenges the way researchers think about and treat leukemia. While more work is needed to correlate the gene expression profiles of extramedullary tumors with those of bone marrow tumors, it could lead to the identification of gene signatures (i.e., biomarkers) that predict extramedullary involvement and point to potential improvements in treatment for leukemia patients.
Read the paper: Cunningam I, Hamele-Bena D, Guo Y et al. (2019) Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites. Am J Hematol 94:1200–1207.
1. Paget S (1889) The distribution of secondary growths in cancer of the breast. The Lancet.