CLEVELAND — Lineage-switching is a mechanism that can lead to treatment resistance in chronic lymphocytic leukemia (CLL), and, though it’s a rare occurrence, it can be fatal.
The ability of CLL cells to convert to different cell types makes it challenging to treat this type of cancer. CLL can occasionally “transdifferentiate” into clonally related histiocytic sarcoma (a myeloid neoplasm) or acute myeloid leukemia (AML). These patients often present with advanced disease and have a poor prognosis because of difficulties in making a definitive diagnosis and lack of standard treatment.
A study published in the journal Blood Advances examined CLL transdifferentiating into clonally related myeloid cells (histiocytic sarcoma or acute myeloid leukemia). The study demonstrates for the first time that CLL cells can dedifferentiate to myeloid cells.1
“Our finding indicates that CLL cells can become resistant to therapy through lineage switching, which renders the original therapy ineffective,” Chen Zhao, MD, PhD, associate professor in the Department of Pathology at Case Western Reserve University in Cleveland, told U.S. Medicine. “Cancer therapy resistance is associated with cancer cell heterogeneity and plasticity, which frequently correlate with more aggressive phenotypes and poor prognosis. Patients with B cell neoplasms (lymphoma or leukemia) occasionally develop clonally-related myeloid neoplasms after treatment. Reports indicate that 2.9 to 8% of patients with B-ALL had lineage switching after treatment. How to target these converted myeloid neoplasms is largely unknown due to the absence of good model systems to investigate the underlying process.”
The cases in the study were collected from Zhao’s daily clinical service while working at the Department of Pathology at the University of Iowa. He encountered two cases where patients with a long history of CLL developed AML during treatment.
Investigating the underlying mechanisms of B-myeloid conversion will contribute to a better understanding of therapy resistance. Almost all of these cases occur post therapy. In general, patients with converted myeloid neoplasms have poor prognosis, Zhao wrote in an email.
The study’s most important finding is that B-myeloid conversion is through dedifferentiation, then redifferentiation, processes. Converted myeloid neoplasms and lymphoid neoplasms are clonally-related, Zhao explained in an email.
“Unraveling the mechanisms underlying B-myeloid lineage switching will lead to identification of effective specific pathway inhibitors to prevent and target these uncommon, but fatal converted myeloid neoplasms,” Zhao wrote in an email. “Prevention and targeting B-myeloid conversion is critical to treat these patients. We are continuing to investigate the underlying molecular mechanisms to target cancer cell plasticity.”
- Dong Q, Xiu Y, Bossler A, Syrbu S, Wang H, Xue W, Zhao J, Li Q, Jin M, Wang L, Boyce B, Sakr H, Ansari MQ, Zhao C. CLL dedifferentiation to clonally related myeloid cells. Blood Adv. 2020 Dec 22;4(24):6169-6174. doi: 10.1182/bloodadvances.2020002726. PMID: 33351112; PMCID: PMC7756991.