Parameter perturbations in a post-treatment chronic myeloid leukemia model capture the essence of pre-diagnosis A-bomb survivor mysteries

Abstract

A model of post-diagnosis chronic myeloid leukemia (CML) dynamics across treatment cessations is applied here to pre-diagnosis scenarios of A-bomb survivors. The main result is that perturbing two parameters of a two-state simplification of this model captures the essence of two A-bomb survivor mysteries: (1) in those exposed to > 1 Sv in Hiroshima, four of six female onsets arose as a cluster in 1969–1974, well after 5–10-year latencies expected and observed in two of six female- and nine of ten male cases (about one background case was expected in this high-dose cohort); and (2) no Nagasaki adult cases exposed to > 0.2 Sv were observed though about nine were expected (~ 1.5 background + ~ 7.5 radiation-induced). Overall, it is concluded that: (1) whole-body radiation co-creates malignant and benign BCR-ABL clones; (2) benign clones are more likely to act as anti-CML vaccines in females than in males; (3) the Hong Kong flu of 1968 (and H3N2 seasonal flu thereafter) exhausted anti-CML immunity, thereby releasing radiation-induced clones latent in high-dose Hiroshima females; and (4) benign cells of 1–2 are CD4 + as human T-cell leukemia-lymphoma virus-1 endemic to Nagasaki but not Hiroshima expands numbers of such cells. The next goal is to see if these conclusions can be substantiated using banked A-bomb survivor blood samples.

What do atomic bomb survivors teach us about therapy-free remission in people with chronic myeloid leukaemia?

“…Clustering may have occurred because the 1968 Hong Kong flu pandemic entered Japan in 1969, the same year as the first delayed female Hiroshima CML onset case, and evolved into the H3N2 seasonal flu [ 7 ]. Put otherwise, we hypothesise that H3N2 exhausted anti-CML immunity in the A-bomb survivors and that this released latent neoplastic radiation-induced BCR::ABL1 -positive cells and thus clustered delayed onset Hiroshima females [ 8 ]. A study of mice provides some support for this idea [ 9 ].…”

“…This hypothesis has 3 contingencies: (1) CD4-positive cells expanded in numbers before the bombings because of endemic HTLV-1 infection and were the target of radiation-induced BCR::ABL1 -positive non-neoplastic clones; (2) numbers of such cells were sufficiently high such that every adult exposed to >0.2 Sieverts (Sv) in Nagasaki developed ≥1 CD4-positive cell with a BCR::ABL1 translocation and consequently developed immunity to CML including CML unassociated with radiation exposure; and (3) relative to Hiroshima, CD4-positive cells were more effective in both sexes in Nagasaki because there they expressed not only BCR::ABL1 but also HTLV-1-infection-related genes. Put otherwise, we hypothesise CD4-positive T-cells delivered BCR::ABL1 immunogenic peptides to invoke immunity, HTLV-1 was an adjuvant that boosted anti-CML immunity, and CD4-positive, BCR::ABL1 -positive clones were self-limiting by acting as auto-vaccines [ 8 ].…”

“…A study of people attempting TFRs claims to have identified 3 types of subjects [ 4 ]. We suggest these cohorts correspond to people who are Hiroshima-male-like (incapable of holding a TFR), Hiroshima-female-like (capable of holding a TFR but at random times of immuno-suppression this TFR can be lost), and Nagasaki-like (capable of holding TFRs robustly across immuno-compromising perturbations) [ 8 ]. To further connect A-bomb survivors to these TFR cohorts we focus on the founding LSC, which is likely a very primitive, TKI-resistant cell [ 11 ].…”

“…Thus, as low as 11% (5/44) of TFRs may have been by immuno-control. Of these, half might be Nagasaki-like and half Hiroshima-female-like [ 4 , 8 ]. Only the latter (~5% of TFRs) are expected to be susceptible to relapses via flu or COVID infections.…”

“…Onset clustering in Hiroshima and cases missing in Nagasaki are hard to explain [ 5 ]. Evidence for our explanation includes the alternatives having inconsistencies [ 8 ]. Via our explanation, A-bomb survivors teach us to look for a CD4-positive cell role in CML immunity.…”