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Frontiers in Hematology ·

Volume 5 - 2026 | https://doi.org/10.3389/frhem.2026.1814036

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

  • Emily Proudman1
  • Philip Savage1*corresponding author
  1. Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Abstract

At present, the detailed mechanisms of how cytotoxic chemotherapy routinely produces cure in a limited number of malignancies whilst causing only more modest effects on the majority of cancers and healthy normal cells are uncertain. In this article, we reviewed published information regarding the impact of chemotherapy exposure on the viability of the cells of origin of a number of chemotherapy-curable malignancies. In general, these cells are difficult to study as they are transient, challenging to study ex vivo, and anatomically relatively inaccessible. In B-cell and T-cell acute lymphoblastic leukaemia, it is apparent that exposure to DNA damaging chemotherapy or radiotherapy results in near total loss of the respective cells of origin of pro-B cells and double-positive (DP) thymocytes within 2 days. However, these cells are rapidly replaced from the chemotherapy-resistant bone marrow stem cells. In diffuse large B-cell lymphoma, the germinal centre cells of origin are naturally poised on the edge of apoptosis, with a half-life of approximately 6 h, making in vitro study impractical. The probable cell of origin of testicular cancer is the OCT4 + stem cell, which shows similar sensitivity to chemotherapy to that of malignant cells, with total loss of these stem cells upon exposure to BEP (bleomycin, etoposide, and platinum/cisplatin) combination chemotherapy. Overall, it appears that chemotherapy-curable malignancies do not acquire a high degree of sensitivity to chemotherapy on their change to the malignant phenotype; rather, they maintain the high sensitivity of their cells of origin. These findings are in keeping with our previous observations that the high degree of chemotherapy sensitivity follows the dramatic changes in apoptotic sensitivity that accompany the genetic manipulations of variable–diversity–joining (VDJ) recombination, somatic hypermutation, meiosis, and nuclear fusion occurring in these normal healthy but transient cells.

Keywords

Introduction

Cytotoxic DNA-damaging chemotherapy has been routinely curative for a select group of malignancies for over 50 years (1). However, despite extensive research, the list of routinely curable metastatic cancers is limited, and currently, cytotoxic chemotherapy treatment does not offer cure in the large majority of cases of advanced cancer (2).

The scientific explanation behind this divergence in outcome is not yet fully elucidated. At present, a dominant research paradigm focuses on the intrinsic and acquired chemotherapy resistance in non-curable malignancies (3). In contrast, there has been limited research examining potential mechanisms that could explain the heightened sensitivity of chemotherapy-curable malignancies (4, 5).

A number of recent publications have presented a strong argument against the rate of cell division being of central importance to chemotherapy curability (6, 7). However, the answer to the key question of the mechanisms by which these tumour cells are killed whilst normal cells are apparently spared remains unclear (7). It is possible that an insight into this apparent paradox may be gained by looking at the intrinsic properties of the relatively poorly studied cells of origin of these chemotherapy-curable malignancies.

We have previously argued that the malignancies that are routinely curable with chemotherapy each arise from a transient specialised developmental cell that is in the midst of a specific DNA manipulation. These genetic manipulations appear to be closely associated with a naturally occurring high sensitivity to apoptosis (4). In addition, following the change to the malignant phenotype, the usual developmental progression of these transient cells is halted. As a result, the newly malignant cells remain frozen at their developmental point, with much of the epigenetic phenotype of the cell of origin, including the heightened sensitivity to apoptosis, still present (8, 9).

Whilst this theory provides a realistic conceptual explanation and interpretation for this complex scenario, relevant data on the characteristics of the cells of origin of chemotherapy-curable malignancies with regard to their sensitivity to chemotherapy have been limited.

As can be seen in Table 1, the cells of origin of the chemotherapy-curable malignancies are transient, difficult to access, and not readily amenable to routine in vitro characterisation and experimentation.

Table 1. Clinical and scientific information on the main chemotherapy-curable malignancies.

MalignancyCell of originGenetic eventLocationChemotherapy cure rate
B-ALLPro-B cellVDJ of Ig genesBone marrow90% in children (10)30% in adults (11)
T-ALLDP thymocytesVDJ of TCR genesThymus90% in children (12)50% in adults (13)
DLBCL/HLGerminal centre B cellsSHM/class switchingLymph node spleenDLBCL: 65% (14)HL: 85% (15)
Testicular cancerOCT4+ stem cellsMeiosisTestisSeminoma: 95% (16)NSGCT: 87% (16)
Gestational malignanciesTrophoblast cellsNuclear fusionCells of conceptionMP: 100% (17)CC: 95% (18)PSTT: 49% (19)

The unique genetic event associated with the relevant malignancy is shown along with the anatomical location at which this occurs. The cure rates with modern chemotherapy treatment are displayed, with the majority of the diagnoses having very high cure rates, although those for B-cell and T-cell ALL vary appreciably between children and adults.

B-ALL, B-cell acute lymphoblastic leukaemia; T-ALL, T-cell acute lymphoblastic leukaemia; DLBCL, diffuse large B-cell lymphoma; HL, Hodgkin’s lymphoma; DP, double positive; VDJ, variable–diversity–joining; TCR, T-cell receptor; SHM, somatic hypermutation; NSGCT, non-seminomatous germ cell tumour; MP, molar pregnancy; CC, choriocarcinoma; PSTT, placental site trophoblastic tumour.

Chemotherapy sensitivity of the cells of origin of chemotherapy-curable malignancies

There are some previously published data that can be reviewed to provide insights into the unusual biology of these specialised precursor cells, in particular their natural extreme sensitivity to cytotoxic chemotherapy.

In this review, we will explore the characteristics of the transient cells of origin of chemotherapy-curable malignancies to explore how these may impact the heightened chemotherapy sensitivity of their associated malignancies.

Figure 1 demonstrates the developmental pathway of normal B cells along with the associated malignancies and the timing of the key genetic processes of variable–diversity–joining (VDJ) recombination and somatic hypermutation (SHM).

B-cell developmental pathway showing the cells of origin of the associated malignancies, the cure rates with chemotherapy, and the relationship with variable–diversity–joining (VDJ) and somatic hypermutation (SHM) activity. The malignancies that arise from the cells of origin involved with either VDJ rearrangement or SHM are associated with high chemotherapy cure rates, whilst those malignancies arising from cells of origin that are not undergoing these processes are generally incurable.
Figure 1. B-cell developmental pathway showing the cells of origin of the associated malignancies, the cure rates with chemotherapy, and the relationship with variable–diversity–joining (VDJ) and somatic hypermutation (SHM) activity. The malignancies that arise from the cells of origin involved with either VDJ rearrangement or SHM are associated with high chemotherapy cure rates, whilst those malignancies arising from cells of origin that are not undergoing these processes are generally incurable.

B-cell ALL/pro-B cell

B-cell acute lymphoblastic leukaemia (B-ALL) has been routinely curable with combination chemotherapy since the 1960s. The current cure rates approach 90% for children and 50% for adults (10, 11).

The predominant cell of origin of B-ALL is pro-B cell (20), which is an early B cell that is closely involved with the VDJ rearrangement process of immunoglobulin genes (21). The VDJ process involves cutting and recombination of the immunoglobulin genes, a complex process involving the RAG1 and RAG2 proteins (22).

Previous studies have demonstrated that the epigenetic phenotype of B-ALL cells is very similar to that of pro-B cells and that the onset of malignancy blocks the normal ongoing B-cell development (8, 23). As a result, much of the pro-B-cell epigenetic profile at the time of malignant transformation is retained. Additional studies have demonstrated that the process of VDJ rearrangement can still be ongoing, albeit at a low level, in ALL cells (24). This close link between VDJ activity and curability across the range of early leukaemias has been demonstrated with VDJ activity clearly associated with a favourable prognosis in cases of early leukaemia (25).

An insight into the chemotherapy sensitivity of normal pro-B cells can be obtained from the 2001 publication of Zandvoort et al. (26). In this study, the impact of a single dose of chemotherapy on the number of B cells at differing stages of development in the bone marrow and spleen of rats was examined.

As shown in Figure 2, prior to chemotherapy exposure, the pro-/pre-B cells are readily detectable, comprising approximately 12% of the cells in the bone marrow. However, when assayed 2 days after exposure to chemotherapy, the proportions of pro-/pre-B cells and newly formed B cells in the bone marrow have fallen to nearly zero. Further follow-up samples indicate that the number of pro-/pre-B cells returns close to their pretreatment value by day 15 following cisplatin treatment and by day 24 with exposure to cyclophosphamide, an agent that has greater toxicity to haematological stem cells (HSCs).

*In vivo* sensitivity of rat bone marrow pro-/pre-B cells to a single dose of chemotherapy. Data are presented as the number of pro-/pre-B cells as a percentage of the total number of B cells present. The data demonstrate a near total loss of pro-/pre-B cells by day 2, but with near full recovery by day 15 after cisplatin exposure and by day 24 for cyclophosphamide. Data taken from Zandvoort et al. (26).
Figure 2. In vivo sensitivity of rat bone marrow pro-/pre-B cells to a single dose of chemotherapy. Data are presented as the number of pro-/pre-B cells as a percentage of the total number of B cells present. The data demonstrate a near total loss of pro-/pre-B cells by day 2, but with near full recovery by day 15 after cisplatin exposure and by day 24 for cyclophosphamide. Data taken from Zandvoort et al. (26).

The data in this publication confirm that these normal non-malignant pro-/pre-B cells, the cells of origin of B-ALL, are already extremely sensitive to the impact of cytotoxic chemotherapy. In response to treatment, these is a rapid near total loss of these cell numbers, but with a subsequent prompt repopulation from their precursors, the HSCs, which are appreciably more resistant to cytotoxic chemotherapy (27).

In contrast, the B-cell malignancies arising earlier and later in the developmental pathway show lower chemotherapy cure rates. Acute undifferentiated leukaemia is a rare malignancy arising from an early stem cell precursor, in which the VDJ machinery is only partially activated (28), which has childhood chemotherapy cure rates of approximately 80% and adult cure rates of only 20% (29). The malignancy arising from naive B cells after the completion of VDJ is unmutated chronic lymphocytic leukaemia (U-CLL), which can have long-term survival with chemotherapy; however, cure does not occur (30).

Diffuse large B-cell lymphoma/germinal centre B cell

After VDJ recombination of the immunoglobulin gene has been completed, the B-cell developmental pathway next passes through to the phase of naive B cells. At this point, neither the VDJ or SHM machinery is active, and the malignancies that can arise from these cells are mantle cell lymphoma and U-CLL (31, 32). These diagnoses have appreciable sensitivity to conventional cytotoxic chemotherapy treatment; however, a curative outcome is not a realistic expectation (33, 34).

The next key stage of B-cell genetic development includes SHM and class switching of the immunoglobulin genes, which occurs in the germinal centre of the lymph nodes and spleen. This second genetic process is driven by the activation-induced deaminase (AID) enzyme that initiates the process of SHM (35).

The processes of SHM and class switching are closely associated with very high levels of natural apoptosis that results in the average survival of a germinal centre B cell being only 6 h (36). The B-cell malignancies that arise during these processes are diffuse large B-cell lymphoma (DLBCL) (37) and Hodgkin’s lymphoma (HL), both of which have high cure rates with chemotherapy (14, 15).

With the extremely short natural history of normal germinal centre B cells, with an apoptotic rate of 3% every 20 minutes, there is no direct data looking at the impact of chemotherapy or radiotherapy on the survival of these cells. However, there are data from the 2001 publication by Zandvoort et al. that demonstrated the high sensitivity to chemotherapy of other closely related B-cell types that occur on the B-cell developmental pathway either shortly before or after the germinal centre process (26).

As can be seen in Figure 3, the overall lymph node lymphocyte count is relatively unaffected by cisplatin exposure. In contrast, the early recirculating follicular B (EFR-B) cells, which are developmentally close to the completion of SHM, have a high degree of sensitivity to cisplatin chemotherapy, with their number falling to 27.1% of the starting number on day 7 and recovering to 85.9% on day 15. In contrast, the recirculating follicular B (RF-B) cells and marginal zone B (MZ-B) cells that have completed SHM appear essentially unaffected by cisplatin chemotherapy, with their numbers remaining stable during the course of the experiment.

*In vivo* sensitivity of rat splenic B cells to a single dose of chemotherapy. Data are presented as the number of B-cell subgroups as a percentage of their pre-chemotherapy total number. Exposure to a single dose of cisplatin leads to a major reduction in the number of early recirculating follicular B (EFR-B) cells by 73% on day 7, but with only a minor impact on recirculating follicular B (RF-B) and marginal zone B (MZ-B) cells, which are developmentally more distant to the actual germinal centre B cells. By day 15, the cell numbers have returned to near pretreatment levels. Data taken from Zandvoort et al. (26).
Figure 3. In vivo sensitivity of rat splenic B cells to a single dose of chemotherapy. Data are presented as the number of B-cell subgroups as a percentage of their pre-chemotherapy total number. Exposure to a single dose of cisplatin leads to a major reduction in the number of early recirculating follicular B (EFR-B) cells by 73% on day 7, but with only a minor impact on recirculating follicular B (RF-B) and marginal zone B (MZ-B) cells, which are developmentally more distant to the actual germinal centre B cells. By day 15, the cell numbers have returned to near pretreatment levels. Data taken from Zandvoort et al. (26).

Alongside these chemotherapy-related data, there are additional data obtained for staurosporine, an alternative cytotoxic agent that produces rapid and extremely high levels of apoptosis in germinal centre B cells (36). Whilst there are no direct data on the impact of conventional cytotoxic chemotherapy on germinal centre B-cell viability, it appears reasonable to assume that these cells perched on the edge of a natural apoptotic death are rapidly and extensively killed by exposure to cytotoxic chemotherapy.

T-cell ALL/double-positive thymocyte

T-cell ALL (T-ALL) is a rarer diagnosis than its B-cell counterpart, but shares similar therapeutic characteristics with a high cure rate, approaching 90% in children (12) but with appreciably lower success rates (50%) in adults (13). The common cells of origin of T-ALL are double-positive (DP) thymocytes (38). As shown in Figure 4, these cells occur early in T-cell development and are characterised by the expression of both CD4 and CD8 cell surface markers. DP thymocytes are in the process of VDJ rearrangement of the T-cell receptor (TCR) genes at the time of malignant transformation (39). In parallel to the scenario in B-ALL, the ongoing VDJ activity can be detected in cases of T-ALL (40).

T-cell developmental pathways showing the cells of origin of the associated malignancies, the cure rates, and the relationship with variable–diversity–joining (VDJ) activity. The malignancies that arise whilst VDJ activity is either starting or at full activity have high chemotherapy cure rates, whilst those occurring after VDJ is complete are not curable. Of note is that ALK+ T anaplastic large cell lymphoma is not included due to the uncertainty regarding its cell of origin.
Figure 4. T-cell developmental pathways showing the cells of origin of the associated malignancies, the cure rates, and the relationship with variable–diversity–joining (VDJ) activity. The malignancies that arise whilst VDJ activity is either starting or at full activity have high chemotherapy cure rates, whilst those occurring after VDJ is complete are not curable. Of note is that ALK+ T anaplastic large cell lymphoma is not included due to the uncertainty regarding its cell of origin.

The sensitivity of these cells and other related early T-cells to DNA damage from low-dose radiation (9.5 Gy) has been assessed in a murine model (41). As shown in Table 2, double-negative (DN) and DP cells, which are in the process of VDJ rearrangement, have the highest radiation kill rates, with 92.08% for DP and 76.38% for DN. In contrast, single-positive cells that have completed TCR recombination and give rise to mature T-cell lymphomas are appreciably more radiation-resistant, with kill rates of 59.83% for CD4+ and only 19.63% for CD8+.

Table 2. Relatively apoptotic sensitivity of cells in the T-cell developmental pathway demonstrated from a murine model with exposure to a single radiation dose of 9.5 Gy (41).

Thymocyte cell typeCell death with radiation at 9.5 Gy
CD4−CD8− (DN)76.38%
CD4+CD8+ (DP)92.08%
CD4+CD8−59.83%
CD4−CD8+19.63%

Double-positive (DP) cells, which are in the midst of variable–diversity–joining (VDJ) rearrangement of the T-cell receptor (TCR) gene and are the common cells of origin for acute T-cell lymphoblastic leukaemia (T-ALL), show the highest level of cell death with radiation (92.08%). Single-positive cells that have completed TCR recombination and give rise to mature T-cell lymphomas are appreciably more resistant to radiation, with death rates of 59.83% for CD4 and 19.63% for the CD8 cells.

A similar study that used lower doses of radiation also confirmed the heightened sensitivity of DP cells (42). Additional analysis indicated that the cells with the greatest sensitivity to radiation are individual single-positive (ISP) cells, which are intermediary cells between the DN and DP thymocyte stages. The high level and rapid-onset cell death of ISP cells at low-dose radiation (1.5–6 Gy) is demonstrated in Figure 5, along with the rapid recovery in cell numbers that occurred by day 4 (42).

*In vivo* sensitivity of individual single-positive (ISP) developmental thymocytes from C57BL/6 mice to low-dose radiation (1.5, 4, and 6 Gy). The frequency of ISP cells within the CD8+ populations falls rapidly upon exposure to radiotherapy, demonstrating a near total loss of cells by day 2, but with recovery via repopulation from stem cells by day 4. Data taken from Gentil Dit Maurin et al. (42).
Figure 5. In vivo sensitivity of individual single-positive (ISP) developmental thymocytes from C57BL/6 mice to low-dose radiation (1.5, 4, and 6 Gy). The frequency of ISP cells within the CD8+ populations falls rapidly upon exposure to radiotherapy, demonstrating a near total loss of cells by day 2, but with recovery via repopulation from stem cells by day 4. Data taken from Gentil Dit Maurin et al. (42).

Variations in the radiation sensitivity of the T-ALL cells of origin are reflected in the sensitivity of their associated malignancies to chemotherapy. Conventional T-ALL, which generally arises from DP thymocytes, is associated with a cure rate of 90% in children. In contrast, early T-cell precursor acute lymphoblastic leukaemia (ETP-ALL), which arises earlier in the T-cell development pathway at the DN thymocyte stage where the VDJ activity is less intense, is appreciably less sensitive to standard cytotoxic chemotherapy treatment (43).

The maturing single-positive (CD4 and CD8) thymocytes that have completed VDJ rearrangement are less sensitive to radiation, and the post-VDJ mature T-cell lymphomas that arise after this point are characteristically of modest chemotherapy sensitivity (44).

Testicular cancer/arrested gonocyte

Advanced testicular cancer has been curable with combination chemotherapy since the early 1960s (45), with recent studies indicating overall cure rates for metastatic seminoma and non-seminoma of 95% and 87%, respectively (16, 46).

The cell of origin for testicular cancer is thought to be an aberrant abnormal gonocyte, a developmental cell that has failed to mature normally into healthy pre-spermatogonia (47).

A recently published mouse model has examined a number of characteristics of these cells, including their sensitivity to chemotherapy treatment (48). In contrast to the generally high level of resistance to chemotherapy observed in standard cancer stem cells, OCT4+ testicular cancer stem cells are extremely sensitive to chemotherapy. As can be seen in Figure 6, exposure of these cells to single-agent cisplatin chemotherapy produces a major reduction in the number of cells, whilst multi-agent BEP (bleomycin, etoposide, and platinum/cisplatin) chemotherapy results in the total loss of these testicular cancer precursor cells.

Sensitivity of OCT4<sup>+</sup> testicular cancer stem cells to single-agent and combination chemotherapy. The graph shows the percentage of OCT4<sup>+</sup> stem cells within tumours in a murine model of testicular cancer. The mice were treated with either no treatment, with cisplatin alone, or with BEP (bleomycin, etoposide, and platinum/cisplatin) combination chemotherapy. In untreated mice, the OCT4<sup>+</sup> stem cells are readily identifiable. With cisplatin alone, a major reduction in numbers is seen, whilst there is a total loss of the OCT4<sup>+</sup> stem cells upon treatment with BEP chemotherapy. Data taken from Pierpoint et al. (48).
Figure 6. Sensitivity of OCT4+ testicular cancer stem cells to single-agent and combination chemotherapy. The graph shows the percentage of OCT4+ stem cells within tumours in a murine model of testicular cancer. The mice were treated with either no treatment, with cisplatin alone, or with BEP (bleomycin, etoposide, and platinum/cisplatin) combination chemotherapy. In untreated mice, the OCT4+ stem cells are readily identifiable. With cisplatin alone, a major reduction in numbers is seen, whilst there is a total loss of the OCT4+ stem cells upon treatment with BEP chemotherapy. Data taken from Pierpoint et al. (48).

There is little clinical data on the impact of chemotherapy on the human testicular cancer cells of origin. However, a study that examined the varying impacts of low-dose radiotherapy on the survival of developmental cells along the spermatogenesis pathway demonstrated a major degree of enhanced cytotoxicity of the cells actively involved in meiosis (49, 50).

Gestational malignancies

Arising from the cells of conception, gestational malignancies form a group of rare but highly curable cancers. Whilst there are limited in vitro data examining the chemotherapy sensitivity of the newly fertilised zygote, there are considerable routine clinical data demonstrating the extreme sensitivity of these cells of early pregnancy to exposure to DNA-damaging chemotherapy.

A single dose of methotrexate is widely used both in the treatment of ectopic pregnancy and elective termination and is highly effective (51, 52). The typical dose employed is 50 mg, which is appreciably lower than the doses used in cancer treatments. However, the degree of chemosensitivity changes rapidly during pregnancy, and by the end of the first trimester, full-dose combination chemotherapy can be used safely in the treatment of maternal malignancies (53).

Whilst gestational malignancies all arise from the cells of conception early in development, it appears that the actual time point of malignant transformation varies with each specific diagnosis. In molar pregnancies, the malignant change occurs essentially at the point of fertilisation. In contrast, in gestational choriocarcinoma, the malignant transformation is believed to occur in cytotrophoblast cells (54), a cell line that first appears approximately on day 8. Similarly, in placental site trophoblastic tumours, the malignant change arises from the intermediate trophoblast cells (55), which are present after day 12 (56).

Data from patient treatment series, as shown in Figure 7, indicate that the overall chemotherapy cure rates declined across this series, as the point of malignant transformation moved from the point of conception, falling from 100% for molar pregnancies to 94% for gestational choriocarcinoma and 49% for placental site trophoblast tumours (17–19).

Chemotherapy cure rates for gestational malignancies, demonstrating a fall from 100% for post-molar pregnancy gestational trophoblastic neoplasia (GTN) to 94% for gestational choriocarcinoma and 49% for placental site trophoblastic tumour (PSTT). The reduction in the cure rates with chemotherapy appears to be associated with the temporal distance of the cells of origin from the time of fertilization and nuclear fusion.
Figure 7. Chemotherapy cure rates for gestational malignancies, demonstrating a fall from 100% for post-molar pregnancy gestational trophoblastic neoplasia (GTN) to 94% for gestational choriocarcinoma and 49% for placental site trophoblastic tumour (PSTT). The reduction in the cure rates with chemotherapy appears to be associated with the temporal distance of the cells of origin from the time of fertilization and nuclear fusion.

Other chemotherapy-curable malignancies

In addition to the malignancies discussed above, a small number of other cancer types are routinely curable with conventional cytotoxic chemotherapy treatment. These include the rare childhood malignancies ovarian germ cell tumours and ALK-positive T-cell lymphoma. For these malignancies, the cells of origin are either uncertain or have not been studied in detail to date. Further information on these malignancies and the potential pathways and mechanisms involved is discussed in our earlier publication (4).

Role of environmental and additional genetic components on chemotherapy curability

In addition to the high chemotherapy sensitivity of the cancer cells arising from these naturally sensitive cells of origin, chemotherapy-curable cancers also generally have additional favourable characteristics with regard to a number of genetic and microenvironmental factors that can additionally influence sensitivity to chemotherapy.

In contrast to the scenario in common epithelial malignancies where mutations of the p53 tumour suppressor gene are frequent (57), p53 is rarely mutated in chemotherapy-curable malignancies. In gestational tumours, where p53 appears to have a key role in normal trophoblast cell development (58), mutations in p53 have been documented to be very rare (59, 60). Similarly, in germ cell tumours where p53 activity has a central role in meiosis-related DNA damage recognition (61), mutations in p53 are rare both in testicular cancer (62) and ovarian germ cell tumours (63). Similarly, mutations in p53 are also rare in acute leukaemia (64) and DLBCL, where mutations are associated with an inferior prognosis (65).

However, it is also apparent that normal unmutated p53 is also routinely present in a number of closely related malignancies that are not curable with cytotoxic chemotherapy, including mantle cell lymphoma (66) and myeloma (67).

Alongside these genetic issues, the characteristics of the tumour microenvironment (TME) including hypoxia, pH, and extracellular matrix proteins can also have an important impact on the response to chemotherapy in many tumours (68, 69).

It is possible that some individual tumour-related TME issues may help contribute to chemotherapy curability, such as the low HIF-1α production in response to hypoxia (70) and the enhanced macrophage degradation of the extracellular matrix in testicular cancer (71).

The microenvironments associated with chemotherapy-curable malignancies are likely to vary appreciably with individual diagnosis. In B- and T-cell ALL, the majority of malignant cells are in the circulation or the bone marrow, whilst germ cell tumours can form large lymph node masses. As a result, the nature of the TME interactions is likely to be quite variable across the range of diagnoses, and due to the rarity of these diagnoses and their high cure rates, this has not been a major area of research (72).

Viewed overall, it may be reasonable to suggest that the pro-apoptotic epigenetic changes inherited from the cell of origin determine the potential for chemotherapy curability and that this sensitivity is supported by a lack of mutation in the p53 pathways and the absence of any powerful detrimental impact of the TME in these malignancies.

Summary

Cytotoxic chemotherapy treatment has been routinely curative for a select group of malignancies for over 50 years. The exact processes occurring within malignant cells that lead to this very high sensitivity to DNA damage are yet to be fully described. As a result, the mechanisms by which these tumour cells are killed remarkably effectively whilst normal cells are apparently spared have remained a recurring question.

In this review, we have looked at the available information relating to the chemotherapy sensitivity of the cells of origin of the chemotherapy-curable malignancies.

The laboratory and animal data demonstrate that the healthy cells of origin for B-cell and T-cell ALL, for DLBCL, and for testicular cancer are each highly sensitive to chemotherapy, with these precursor cells rapidly disappearing upon DNA damaging chemotherapy or radiotherapy exposure. Fortunately, the cells of origin of haematological malignancies are rapidly repopulated from chemotherapy-resistant stem cells, whilst the testicular cancer cells of origin are replaced on a similar but a much slower pathway.

In gestational malignancies, there are extensive clinical data to indicate the heightened chemotherapy sensitivity of the early pregnancy cells of origin of these malignancies and how this declines rapidly during the first trimester.

From the available data, it is reasonable to conclude that these normal cells that form the cells of origin of the chemotherapy-curable malignancies undergo rapid cell death during chemotherapy exposure. As a result, the extreme sensitivity to chemotherapy observed in these tumours appears to be a direct reflection of the high sensitivity that is naturally seen in their cells of origin. However, as these cells are not easy to monitor or measure in vivo, or in vitro, the amount of data supporting this observation is limited, but interesting.

We have previously hypothesised that the key driver of chemotherapy sensitivity and the induction of apoptosis in both these normal and malignant cells are the epigenetic changes associated with the DNA manipulation processes occurring in these specialised cells.

This scenario is in contrast to the general non-curative response to chemotherapy observed in the majority of common epithelial malignancies and in haematological malignancies where the cell of origin is not involved in DNA manipulation. In these more common malignancies, the cancer stem cells or tumour-initiating cells are characteristically highly resistant to cytotoxic drugs and radiotherapy (73). Further research into the mechanisms that allow the cells of origin to transiently develop the heightened sensitivity to chemotherapy, DNA damage, and induction of apoptosis may provide insights into potential therapeutic avenues.

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Footnotes

Edited by: Valentina Giudice, University of Salerno, Italy

Reviewed by: John M. Perry, Children’s Mercy Kansas City, United States

Lisandra De Oliveira Silva, Federal University of Santa Catarina, Brazil

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Data availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

PS: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. EP: Data curation, Project administration, Resources, Writing – review & editing.

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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, Volume 5. https://doi.org/
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*Correspondence: Philip Savage

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