Stem Cells, Vol. 18, No. 5, iii,
September 2000
© 2000 AlphaMed Press
A Challenge to Solve "Lichtman's Riddles"
Curt I. Civin, M.D., Editor-in-Chief
On August 10, Dr. Marshall Lichtman, distinguished physician scientist, local and international leader, and one of everyone's favorite people, e-mailed me the unsolicited first submission for STEM CELLS Young Turks section. As you may recall from my announcement of the Young Turks section in this column [1], it was Marshall who initially suggested the concept of STEM CELLS Concise Reviews. The concept was immediately adopted, and it was right on. Our high-quality Concise Reviews are a distinguishing feature of the Journal. Thus, what could be more symmetrical (and promising) than for Marshall to endorse and initiate the Young Turks section? I hope you will enjoy Professor Lichtman's clearly elucidated translational bedside-to-bench thoughts on the reciprocal questions of A) why normal hematopoiesis is inhibited in leukemia, and B) why minimal residual leukemia cells may remain quiescent for years.
Many of us have wondered why, in a subset of cases of acute myeloid and (less commonly) lymphoid leukemia, patients present with marrow hypoplasia (reduced hematopoiesis) when they have only a relatively small leukemia cell burden. Marshall asks, "What is the mechanism by which normal hematopoiesis is inhibited in such situations?" What's your answer to this riddle?
My own response would be to begin by hedging, i.e., there may be many mechanisms, specific to the biologic and molecular features of the leukemia clone. But I'd take a wild guess that, in some cases, leukemic blasts might produce Fas ligand (or TNF). There is considerable evidence for expression of Fas (the receptor for Fas ligand) on committed hematopoietic progenitor cells. In this highly speculative scenario, binding of leukemia cell-derived Fas ligand to progenitor cell membrane expressed Fas would trigger apoptotic death of normal hematopoietic progenitor cells. Perhaps only relatively mature progenitors express Fas, or perhaps early stem-progenitor cells are resistant to Fas (e.g., they may express FLIP, an inactive molecular mimic of Caspase 8). If so, the potential to recover normal hematopoiesis after reduction of the leukemia cell burden would be preserved. This model appears easily testable. Do you have the data? Or a better hypothesis?
Professor Lichtman's second riddle involves the conundrum of quiescence of the small residual leukemia cell burden observed in many patients in clinical remission. Perhaps these residual leukemia cells cannot function as leukemia "stem" cells, as might be tested by their (lack of) ability to engraft in immunodeficient mice. As Marshall discusses, these residual leukemia cells may represent "leukemia minor" (a less than maximally transformed cell clone, which requires one or more mutational "hits" to confer the capacity to relapse rapidly). Potentially, this could be tested by cDNA microarray, serial analysis of gene expression (SAGE), representational difference analysis (RDA), or other techniques to compare gene expression in the initial diagnostic leukemia cells versus purified minimal residual leukemia cells present in remission (and versus leukemia cells obtained if relapse occurs). Is this testable?
I hope that many of you will enjoy contemplating "Lichtman's Riddles" and that a lively scholarly dialogue will develop on these (and future Young Turks) themes. I certainly agree with Dr. Lichtman that hypotheses followed by experimental tests of mechanisms of these clinical phenomena might even lead to new strategies in leukemia treatment. "Lichtman's Riddles" was submitted on August 12 and published two weeks later on September 1, 2000. The editors hope that this speed of publication will encourage others to submit their provocative thoughts to the Young Turks section.
References
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Civin CI. Young Turks Forum—for the young and the young at heart (editorial). STEM CELLS 2000;18:ii.
