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Godwits and blast crises: In memory of David Galton

I shall remember David Galton for many things and with great affection but what sticks in my mind is the first thing he taught me – and the last, spaced some 30 years apart. My first contact with David was in the late 1970s whilst I was on something of a crusade about the virtues of immunological dissection of leukaemic subtypes. I thought it was quite clever to be able to distinguish lymphoid and myeloid blast crises and to align lymphoid blast crises with primary acute lymphoblastic leukemias (ALL) with equivalent early B lineage phenotypes and a Philadelphia chromosome [1]. David thought this interesting but was unpersuaded of the supremacy of immunophenotype over morphological phenotype. What he (as well as I, Daniel Catovsky and others) did agree was interesting was the possibility that at least some cases presenting as Ph-positive ALL might in fact be blast crises emerging from clinically covert chronic myeloid leukemia (CML) [1,2]. A few cases that ‘reverted’ to CML after therapy for ALL appeared to support this contention. It turns out that this idea is, at least in part, correct, perhaps specifically for Phþ-ALL with the p210 variant of BCR-ABL1 fusion [3] which ALL has in common with CML. The p190 version of the fusion which we discovered some years later [4] appears to originate predominantly B lymphoid cells [3]. Notwithstanding, this debate sparked off an idea that has had a major influence on my thoughts about de novo acute leukemia in general, and particularly ALL in children: that maybe it always evolves as a kind of blast crisis from a prior benign and silent ‘chronic’ phase of disease. More on that later. David’s extraordinary skill at morphological discrimination, combined with intellectual curiosity, was paralleled by the last gem of a fact he bequeathed to me whilst in north Norfolk where we both had a cottage ‘retreat’. David, as his friends and family well know, was a very enthusiastic and knowledgeable natural historian. For his mentor Sir John Dacie, it was moths and lepidoptera; for David it was ornithology and wader birds. David told me, a few years ago, that he had discovered how to distinguish a bar tailed godwit from a black tailed godwit. I have to say, on this occasion I was unimpressed. My response was along the lines of: isn’t it easy, one is much shorter than the other and has black and white bars on its tail? ‘Oh no,’ replied David, ‘very often all you can see is its head appearing above the reeds.’ He then went on to expound how you could reliably distinguish the two species of godwit by the way they moved their heads, demonstrating this by convincing mimicry. He thought this would make a worthwhile contribution to some ornithological journal but wasn’t confident he could describe in words the critical features of head jerking. Obviously a movie was required, I suggested, preferably with David wearing a long-beaked mask. The point of this anecdote is really this. David inherited the Linnaeus bug (or gene); he was addicted to dissecting and classifying the natural order and diversity of things. Leukemias were obviously, in the medical and social sense, rather more important but similar principles applied to godwits and anything else that moved (and plants that didn’t). This early interest in the covert beginnings of acute leukemia seduced me into spending most of the past two decades trying to uncover what I came to suspect was the clinically silent and benign ‘pre-leukaemic’ origins of ALL, in children. A speculative hypothesis proposing this idea was published in 1988 [5] and by 2003, some 15 years later, the data were sufficiently robust to conclude that we were right. The essence of the idea is summarised in Figure 1. It is sometimes referred to as the minimal ‘2 hit’ model for childhood ALL. The evidence is molecular in nature and comes from studies on identical twins with ALL [6,7], retrospective scrutiny of archived blood spots [8,9] and screening of a large cohort of newborn cord bloods [10]. The data have been reviewed in detail [11,12] and essential details are now confirmed by other groups. Leukemia & Lymphoma, December 2007; 48(12): 2280 – 2294