The following article features coverage from the 2021 Lymphoma, Leukemia & Myeloma Congress. Click here to read more of Hematology Advisor’s conference coverage.

Live “cell-in-cell” interactions appear to have a role in drug resistance, according to the results of a study presented at the virtual 2021 Lymphoma, Leukemia & Myeloma (LL&M) Congress.

“‘Cell-in-cell’ (CIC) describes the microscopic observation of finding one intact cell inside another whole cell which has been observed in the hematopoietic system and malignancies,” according to the authors.   

To study the biological and pathological significance of CIC structures, the investigators used an ex vivo coculture model that mimics the tumor microenvironment and characterized >40 live CIC cases of chronic lymphocytic leukemia (CLL) cells being internalized by bone marrow fibroblast (BMF) cells.

Continue Reading

The investigators labelled CLL and BMF cells with green and red fluorescent cell staining dyes, respectively. They conducted washout assays to assess whether CLL cells can exit internalization and remain alive and transwell migration assays to assess if ibrutinib (Ibr)-resistant CLL cells are more likely to be internalized than Ibr-sensitive cells.

Microscopic imaging of the CLL and BMF cell coculture showed that CLL cells were internalized by BMF cells, and the internalized CLL cells were alive and exhibited long-term within-cell movements. The investigators also confirmed that CLL cells can exit internalization or remain internalized for extended periods of time.

The team found no association between prognostic indicators of CLL (IGHV mutation status or number of cytogenetic abnormalities) and the number of internalized cells per sample.

They went on to demonstrate that while both Ibr-resistant CLL cells and ibrutinib-naïve CLL cells were internalized by BMF cells, significantly more Ibr-resistant CLL cells were internalized than ibrutinib-naive CLL cells. Stimulation of Ibr-resistant or drug-exposed CLL cells with interleukin-15/CpG DNA led to increased CLL cell proliferation and internalization. The investigators demonstrated a positive correlation between CLL cell proliferation and internalization (R2 =0.78; P =.0003).

“Our findings suggest that tumor cells may evade drug killing by sheltering in stromal cells, which eventually leads to disease persistence and future relapse,” the authors concluded. “Our study represents the first report providing data implicating live ‘cell-in-cell’ in drug resistance.”

Read more of Hematology Advisor‘s coverage of LLM 2021 by visiting the conference page.


Franzen C, Vistarop A, Lu P, et al. Shelter in place: live CLL cells inside the bone marrow fibroblasts and its implication in drug resistance. Poster presented at: 2021 Lymphoma, Leukemia & Myeloma Congress; October 19-23, 2021. Presentation PO-18.