Discordant erythropoiesis in CML
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Correspondence 444 References 1 Cervantes F, Colomer D, Vives-Corrons JL, Rozman C, Montserrat E. Chronic myeloid leukemia with thrombocythemic onset: a CML subtype with distinct hematological and molecular features? Leu- kemia 1996; 10: 1241–1243. 2 Kwong YL, Chiu EKW, Liang RHS, Chan V, Chan TK. Essential thrombocythemia with BCR/ABL rearrangement. Cancer Genet Cytogenet 1996; 89: 74–76. 3 Michiels JJ, Prins ME, Hagermeijer A, Brederoo P, van der Meulen J, van Vliet HHD, Abels J. Philadelphia chromosome-positive thrombocythemia and megakaryoblast leukemia. Am J Clin Pathol 1987; 88: 645–652. 4 Richards EM, Bloxham DM, Nacheva E, Marcus RE, Green AR. COMMENT ON PUBLISHED PAPER Discordant erythropoiesis in CML TO THE EDITOR We enjoyed reading the recent leading article by Clarkson et al 1 concerning ‘New understanding of the pathogenesis of CML: a prototype of early neoplasia’ and broadly agree with their ‘Discordant Maturation’ hypothesis. However, we were surprised by their view that our published data on BFU-E in CML 2 were not in line with their thinking. They have found that the majority of erythrocyte progenitors in CML are more mature and less capable of extensive proliferation than com- parable normal erythrocyte progenitors. We reported that BFU-E in CML formed bursts consisting of more subcolonies than normal BFU-E. 2 Assuming, as we do, that commitment to subcolony formation during the growth of an erythroid burst marks a terminal differentiation event, these two statements imply exactly the same relationship between early and late erythroid progenitors. That is, in order for a given cell popu- lation to outnumber its progenitors disproportionately, there must be an increase in its productive capacity either by increasing its probability of self-renewal or by increasing the number of cell doublings separating the two compartments. We would like to take this opportunity to comment further on the interpretation of our methodology, which relies on the number of subcolonies formed per erythroid burst, ranging from one to the maximum observed. According to Clarkson et al, 1 this phenomenon results from the breaking up of the colonies into subunits at later culture times. Against this interpretation, we have made sequential video recordings which show quite clearly that the cells giving rise to the sub- colonies separate prior to the onset of subcolony formation. 3 Another criticism that has been levelled at our methodology is that subcolony formation is simply a function of the density of the supporting methylcellulose. However, if this were cor- rect, it is difficult to understand why different subcolony multi- Correspondence: SB Marley; Fax: 44 181 740 9679 Received 10 September 1997; accepted 25 November 1997 BCR rearrangement in apparent essential thrombocythaemia. Br J Haematol 1993; 85: 625–626. 5 Stoll DB, Peterson P, Exten R, Laszlo J, Pisciotta AV, Ellis JT, White P, Vaidya K, Bozdech M, Murphy S. Clinical presentation and natural history of patients with essential thrombocythemia and the Philadelphia chromosome. Am J Hematol 1988; 27: 77–83. 6 Saglio G, Pane F, Gottardi E, Frigeri F, Buonaiuto M, Guerrasio A, De Micheli D, Parziale A, Fornaci MN, Martinelli G, Salvatore F. Consistent amounts of acute leukemia-associated P190BCR/ABL transcripts are expressed by chronic myelogenous leukemia patients at diagnosis. Blood 1996; 87: 1075–1080. 7 Kwong YL. Association between b3a2 BCR/ABL fusion and chronic myeloid leukemia with thrombocythemic onset: fortuitous or real? Leukemia 1997; 11: 617–618. plicities should be observed with different recombinant cyto- kines but otherwise identical culture conditions. 4 Finally, Clarkson et al 1 have highlighted the response of normal and CML progenitor cells to c-kit ligand (KL). In both cases, addition of KL to Epo increased the size of the colonies formed by BFU-E. Similarly, we have found that KL plus Epo, compared with Epo alone, increases the cellularity of normal BFU-E (7.5-fold; P = 0.0001) 4 although subcolony multiplicity was not increased. In CML, in addition to increased subcolony cellularity, there was a moderate increase in subcolony multi- plicity (unpublished data). SB Marley Department of Haematology JL Lewis Imperial College School of Medicine JM Goldman Hammersmith Hospital, London, UK MY Gordon References 1 Clarkson BD, Strife A, Wisniewski D, Lambek C, Carpino N. New understanding of the pathogenesis of CML: a prototype of early neoplasia. Leukemia 1997; 11: 1404–1428. 2 Marley SB, Lewis JL, Goldman JM, Gordon MY. Abnormal kinetics of colony formation by erythroid burst-forming units (BFU-E) in chronic myeloid leukaemia. Br J Haematol 1996; 93: 878–883. 3 Marley SB, Amos TAS, Gordon MY. Kinetics of colony formation by BFU-E grown under different culture conditions in vitro. Br J Haematol 1996; 92: 559–561. 4 Lewis JL, Marley SB, Blackett NM, Szydlo R, Goldman JM, Gordon MY. Interleukin-3 (IL-3) but not stem cell factor (SCF) increases self-renewal by human erythroid burst-forming units (BFU-E) in vitro. Cytokine (in press).
Transcript of Discordant erythropoiesis in CML
Correspondence
444References
1 Cervantes F, Colomer D, Vives-Corrons JL, Rozman C, MontserratE. Chronic myeloid leukemia with thrombocythemic onset: a CMLsubtype with distinct hematological and molecular features? Leu-kemia 1996; 10: 1241–1243.
2 Kwong YL, Chiu EKW, Liang RHS, Chan V, Chan TK. Essentialthrombocythemia with BCR/ABL rearrangement. Cancer GenetCytogenet 1996; 89: 74–76.
3 Michiels JJ, Prins ME, Hagermeijer A, Brederoo P, van der MeulenJ, van Vliet HHD, Abels J. Philadelphia chromosome-positivethrombocythemia and megakaryoblast leukemia. Am J Clin Pathol1987; 88: 645–652.
4 Richards EM, Bloxham DM, Nacheva E, Marcus RE, Green AR.
COMMENT ON PUBLISHED PAPER
Discordant erythropoiesis in CML
TO THE EDITOR
We enjoyed reading the recent leading article by Clarkson etal1 concerning ‘New understanding of the pathogenesis ofCML: a prototype of early neoplasia’ and broadly agree withtheir ‘Discordant Maturation’ hypothesis. However, we weresurprised by their view that our published data on BFU-E inCML2 were not in line with their thinking. They have foundthat the majority of erythrocyte progenitors in CML are moremature and less capable of extensive proliferation than com-parable normal erythrocyte progenitors. We reported thatBFU-E in CML formed bursts consisting of more subcoloniesthan normal BFU-E.2 Assuming, as we do, that commitmentto subcolony formation during the growth of an erythroid burstmarks a terminal differentiation event, these two statementsimply exactly the same relationship between early and lateerythroid progenitors. That is, in order for a given cell popu-lation to outnumber its progenitors disproportionately, theremust be an increase in its productive capacity either byincreasing its probability of self-renewal or by increasing thenumber of cell doublings separating the two compartments.
We would like to take this opportunity to comment furtheron the interpretation of our methodology, which relies on thenumber of subcolonies formed per erythroid burst, rangingfrom one to the maximum observed. According to Clarksonet al,1 this phenomenon results from the breaking up of thecolonies into subunits at later culture times. Against thisinterpretation, we have made sequential video recordingswhich show quite clearly that the cells giving rise to the sub-colonies separate prior to the onset of subcolony formation.3
Another criticism that has been levelled at our methodologyis that subcolony formation is simply a function of the densityof the supporting methylcellulose. However, if this were cor-rect, it is difficult to understand why different subcolony multi-
Correspondence: SB Marley; Fax: 44 181 740 9679Received 10 September 1997; accepted 25 November 1997
BCR rearrangement in apparent essential thrombocythaemia. Br JHaematol 1993; 85: 625–626.
5 Stoll DB, Peterson P, Exten R, Laszlo J, Pisciotta AV, Ellis JT, WhiteP, Vaidya K, Bozdech M, Murphy S. Clinical presentation andnatural history of patients with essential thrombocythemia and thePhiladelphia chromosome. Am J Hematol 1988; 27: 77–83.
6 Saglio G, Pane F, Gottardi E, Frigeri F, Buonaiuto M, GuerrasioA, De Micheli D, Parziale A, Fornaci MN, Martinelli G, SalvatoreF. Consistent amounts of acute leukemia-associated P190BCR/ABLtranscripts are expressed by chronic myelogenous leukemiapatients at diagnosis. Blood 1996; 87: 1075–1080.
7 Kwong YL. Association between b3a2 BCR/ABL fusion andchronic myeloid leukemia with thrombocythemic onset: fortuitousor real? Leukemia 1997; 11: 617–618.
plicities should be observed with different recombinant cyto-kines but otherwise identical culture conditions.4
Finally, Clarkson et al1 have highlighted the response ofnormal and CML progenitor cells to c-kit ligand (KL). In bothcases, addition of KL to Epo increased the size of the coloniesformed by BFU-E. Similarly, we have found that KL plus Epo,compared with Epo alone, increases the cellularity of normalBFU-E (7.5-fold; P = 0.0001)4 although subcolony multiplicitywas not increased. In CML, in addition to increased subcolonycellularity, there was a moderate increase in subcolony multi-plicity (unpublished data).
SB Marley Department of HaematologyJL Lewis Imperial College School of MedicineJM Goldman Hammersmith Hospital, London, UKMY Gordon
References
1 Clarkson BD, Strife A, Wisniewski D, Lambek C, Carpino N. Newunderstanding of the pathogenesis of CML: a prototype of earlyneoplasia. Leukemia 1997; 11: 1404–1428.
2 Marley SB, Lewis JL, Goldman JM, Gordon MY. Abnormal kineticsof colony formation by erythroid burst-forming units (BFU-E) inchronic myeloid leukaemia. Br J Haematol 1996; 93: 878–883.
3 Marley SB, Amos TAS, Gordon MY. Kinetics of colony formationby BFU-E grown under different culture conditions in vitro. Br JHaematol 1996; 92: 559–561.
4 Lewis JL, Marley SB, Blackett NM, Szydlo R, Goldman JM, GordonMY. Interleukin-3 (IL-3) but not stem cell factor (SCF) increasesself-renewal by human erythroid burst-forming units (BFU-E) invitro. Cytokine (in press).
