**12. Latest evidence of the role of Vitamin C in leukemia**

A recent study provided clear-cut evidence that Vitamin C is a main regulator of hematopoietic stem cell (HSC) function and leukemogenesis. In fact, Agathocleous and co-workers, using a peculiar strategy for isolation of HSCs and hematopoietic progenitor cells (HPCs) from murine bone marrow, showed that HSCs have unusually high levels of Vitamin C, which decline with differentiation [138]. Importantly, human HSCs and multipotent progenitor cells (MPPs), such as murine HSCs, display high Vitamin C levels.

Using "GULO" mice (deficient in Vitamin C because of the lack of gulonolactone oxidase, the last enzyme in the synthesis of Vitamin C starting from glucose), Agathocleous and colleagues have shown that Vitamin C deficiency induces an increased number of HSCs. A FLT3 internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Using "GULO" mice (deficient in Vitamin C because of the lack of gulonolactone oxidase), Agathocleous and colleagues have shown that Vitamin C deficiency induces an increased number of HSCs. Therefore Vitamin C deficiency, and TET2 mutations, are likely to cooperates with FLT3-ITD to induce leukemia development in murine models of FLT3-ITD-driven leukemia. [138].

Given the above evidence, it will be worth mentioning, once more, that the biochemist Irwin Stone, in his book "The healing Factor: Vitamin C against disease," published in 1972 (45 years ago!), had already warned the scientific community on the role of Vitamin C as a main factor in the prevention and treatment of leukemia. In his words, "*In a leukemic, the biochemical stresses of the disease process has reduced the body stores of ascorbic acid to very low levels … Any ascorbic acid circulating in the blood has been scavenged and locked in the excessive numbers of white blood cells contained in the blood. The plasmas level of ascorbic acid is usually zero or close thereto. A zero level in the blood plasma means that the tissues of the body are not being supplied with this most important metabolite. The ascorbic acid contained in the leukocytes are unavailable for the tissues. The tissues are in a condition of biochemical scurvy and this explains why these depleted tissues are so susceptible to the characteristic hemorrhaging of leukemia and the infections that kill so many of the leukaemics. A leukemic is not only suffering from leukemia but also from a bad case of biochemical scurvy. To correct this condition, ascorbic acid has to be administered in sufficiently large doses not only to saturate the excess of white blood cells but to provide adequate spill over into the blood plasma and tissues so that the seriously ill leukemic will be given a fighting chance to combat the disease. This may require the administration of ascorbic acid at the rate of 25 or more grams per day, as noted in the following case of leukemia treated with megascorbic levels of ascorbic acid.*" [3].
