The dominant research paradigm in oncology has traditionally focused on the mechanisms of intrinsic and acquired chemotherapy resistance in non-curable malignancies. Far less attention has been paid to why the curable cancers are so extraordinarily sensitive in the first place. Recent publications have also weakened the classical assumption that rapid cell division is central to chemotherapy curability, leaving the key question unresolved: by what mechanism are these tumour cells killed so effectively while normal cells are apparently spared? Savage and colleagues have previously proposed that each routinely curable malignancy arises from a specialised developmental cell in the midst of a specific DNA manipulation, such as variable–diversity–joining (VDJ) recombination, somatic hypermutation, meiosis or nuclear fusion. These genetic processes are closely associated with a naturally occurring, heightened sensitivity to apoptosis, and when malignant transformation halts the normal developmental progression, the newly malignant cells remain frozen at their developmental point, retaining much of the epigenetic phenotype of their cell of origin, including that apoptotic fragility.

The new review assembles previously published laboratory, animal and clinical data to test whether the healthy cells of origin of chemotherapy-curable malignancies are themselves highly sensitive to cytotoxic chemotherapy. These precursor cells are notoriously difficult to study: they are transient, anatomically relatively inaccessible and not readily amenable to routine in vitro characterisation. Nevertheless, the available evidence paints a strikingly consistent picture across several of the curable cancers.

In B-cell acute lymphoblastic leukaemia (B-ALL), curable in roughly 90 per cent of children and about 30 to 50 per cent of adults, the predominant cell of origin is the pro-B cell, an early B cell engaged in VDJ rearrangement of its immunoglobulin genes, a cutting-and-rejoining process driven by the RAG1 and RAG2 proteins. The epigenetic phenotype of B-ALL cells closely resembles that of pro-B cells, and VDJ activity can still be detected, albeit at low levels, within the leukaemic cells, with VDJ activity clearly associated with favourable prognosis in early leukaemias. Crucially, a 2001 study by Zandvoort and colleagues examined the impact of a single dose of chemotherapy on B cells at different developmental stages in rats. Before treatment, pro-/pre-B cells comprised approximately 12 per cent of bone marrow cells. Just two days after chemotherapy exposure, their numbers, along with those of newly formed B cells, had fallen to nearly zero. The populations recovered close to pretreatment values by day 15 following cisplatin and by day 24 after cyclophosphamide, an agent more toxic to haematopoietic stem cells. The normal, non-malignant pro-B cells, the very cells of origin of B-ALL, were already extremely sensitive to cytotoxic chemotherapy, yet were rapidly repopulated from their precursors, the chemotherapy-resistant haematopoietic stem cells.

The developmental position matters. Acute undifferentiated leukaemia, arising from an earlier stem cell precursor in which the VDJ machinery is only partially activated, has childhood cure rates of approximately 80 per cent but adult cure rates of only 20 per cent. Unmutated chronic lymphocytic leukaemia, arising from naive B cells after the completion of VDJ, can achieve long-term survival with chemotherapy but is not cured. Further along the B-cell pathway, the germinal centre B cells of lymph nodes and spleen undergo somatic hypermutation and class switching, driven by the activation-induced deaminase enzyme. These processes are accompanied by very high levels of natural apoptosis: the average survival of a germinal centre B cell is only about six hours, with an apoptotic rate of roughly 3 per cent every 20 minutes. The malignancies arising during these processes, diffuse large B-cell lymphoma and Hodgkin’s lymphoma, have cure rates of about 65 per cent and 85 per cent respectively. Although the extreme brevity of germinal centre B-cell life makes direct chemotherapy experiments impractical, Zandvoort’s data showed that early recirculating follicular B cells, developmentally close to the completion of somatic hypermutation, fell to 27.1 per cent of starting numbers by day 7 after cisplatin exposure, recovering to 85.9 per cent by day 15, while recirculating follicular B and marginal zone B cells that had completed hypermutation were essentially unaffected. Staurosporine, an alternative cytotoxic agent, produces rapid and extremely high levels of apoptosis in germinal centre B cells, supporting the reasonable assumption that cells perched on the edge of natural apoptotic death are rapidly and extensively killed by conventional chemotherapy.

A parallel story unfolds in T-cell acute lymphoblastic leukaemia (T-ALL), curable in approaching 90 per cent of children but only about 50 per cent of adults. Its common cells of origin are double-positive (DP) thymocytes, which express both CD4 and CD8 markers and are in the midst of VDJ rearrangement of their T-cell receptor genes. In a murine model exposed to a single radiation dose of 9.5 Gy, the cells engaged in VDJ rearrangement showed the highest kill rates: 92.08 per cent for DP cells and 76.38 per cent for double-negative (DN) cells. By contrast, single-positive cells that had completed T-cell receptor recombination were appreciably more resistant, with kill rates of 59.83 per cent for CD4-positive and only 19.63 per cent for CD8-positive cells. Lower radiation doses confirmed the heightened sensitivity of DP cells, and intermediary single-positive cells died rapidly even at 1.5 to 6 Gy, with cell numbers recovering by day 4. These variations in radiation sensitivity are mirrored in the chemotherapy sensitivity of the associated malignancies: conventional T-ALL from DP thymocytes is highly curable, whereas early T-cell precursor acute lymphoblastic leukaemia, arising at the DN stage where VDJ activity is less intense, is appreciably less sensitive to standard treatment, and mature T-cell lymphomas arising after VDJ completion show only modest chemotherapy sensitivity.

Testicular cancer, curable in about 95 per cent of metastatic seminoma and 87 per cent of non-seminomatous germ cell tumour cases, presents perhaps the most direct evidence. Its cell of origin is thought to be an aberrant gonocyte, a developmental cell that has failed to mature normally into pre-spermatogonia. In contrast to the high chemotherapy resistance typical of cancer stem cells in most tumours, OCT4-positive testicular cancer stem cells in a recently published mouse model proved extremely sensitive to chemotherapy: single-agent cisplatin produced a major reduction in cell numbers, while the multi-agent BEP combination of bleomycin, etoposide and platinum resulted in the total loss of these precursor cells. Clinical data on radiotherapy effects along the spermatogenesis pathway similarly demonstrate enhanced cytotoxicity of cells actively involved in meiosis, the very genetic process associated with germ cell tumour development.

Gestational malignancies provide extensive routine clinical evidence of the same principle. A single 50 mg dose of methotrexate, far lower than cancer treatment doses, is highly effective against ectopic pregnancy and early conception cells, and by the end of the first trimester the chemosensitivity has declined so much that full-dose combination chemotherapy can be used safely to treat maternal malignancies. The timing of malignant transformation within this window tracks the cure rates: molar pregnancies, transformed essentially at the point of fertilisation, are cured in 100 per cent of cases; gestational choriocarcinoma, arising from cytotrophoblast cells first appearing around day 8, in about 95 per cent; and placental site trophoblastic tumours, arising from intermediate trophoblast cells present after day 12, in only 49 per cent. The cure rate falls steadily as the point of malignant transformation moves away from conception.

Additional favourable characteristics support this inherited sensitivity. In contrast to common epithelial malignancies, where p53 tumour suppressor mutations are frequent, p53 is rarely mutated in chemotherapy-curable cancers, including gestational tumours, germ cell tumours, acute leukaemias and diffuse large B-cell lymphoma, although normal unmutated p53 is also present in closely related non-curable malignancies such as mantle cell lymphoma and myeloma, indicating that intact p53 alone is insufficient. Tumour microenvironment factors, such as low HIF-1α production in response to hypoxia and enhanced macrophage degradation of extracellular matrix in testicular cancer, may further contribute, though these interactions vary widely across diagnoses and remain under-researched. Taken together, the authors conclude that chemotherapy-curable malignancies do not acquire a high degree of chemotherapy sensitivity upon malignant transformation; rather, they maintain the natural high sensitivity of their transient cells of origin, a fragility driven by the epigenetic changes accompanying VDJ recombination, somatic hypermutation, meiosis and nuclear fusion. Understanding how these specialised cells transiently develop such heightened sensitivity to DNA damage and apoptosis may, the authors suggest, open entirely new therapeutic avenues for the cancers that chemotherapy currently cannot cure.

Subject of Research: Cancer Research

Article Title: The cells of origin of the chemotherapy-curable malignancies are highly sensitive to cytotoxic chemotherapy-mediated cell death

Article References: Proudman, E., & Savage, P. (2026). The cells of origin of the chemotherapy-curable malignancies are highly sensitive to cytotoxic chemotherapy-mediated cell death. Frontiers in Hematology, 5, Article 1814036. https://doi.org/10.3389/frhem.2026.1814036

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1814036

Keywords: chemotherapy, cancer, apoptosis, cells of origin, leukaemia, lymphoma, testicular cancer, germ cell tumours, VDJ recombination, oncology, cells, origin