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Hypoxia suppresses BCR/Abl and selects imatinib-insensitive progenitors within clonal CML populations

Leukemia volume 20, pages 1291–1293 (2006)Cite this article

We previously showed that severe hypoxia enhances the maintenance, in vitro, of normal stem cells capable of short-term hematopoietic reconstitution (Cipolleschi et al.,1, 2 Ivanović et al.,3 and references therein), and that resistance to hypoxia defines hierarchical levels within hematopoietic populations. The study summarized here addressed the questions (a) whether cell subsets endowed with different levels of sensitivity to severe hypoxia were identifiable within clonal chronic myeloid leukemia (CML) cell populations and (b) whether such subsets differed as for BCR/Abl expression and sensitivity to imatinib-mesylate.

Interestingly, LC2 repopulation appeared largely independent of BCR/Abl expression (Figure 2a and b). BCR/Abl phosphorylation slightly increased starting from day 7, when the number of CFC, but not that of viable cells, was increased (1-log) as an effect of transfer to normoxia (Figure 1a and b). Thus, the rescue of BCR/Abl expression in the course of clonal expansion most likely occurred at the CFC level, in keeping with the finding that BCR/Abl expression increases mainly in committed clonogenic progenitors during disease progression.5 Clonal expansion in LC2 eventually led to the return to an imatinib-sensitive state, as observed following the transfer to LC3 (Figure 2a). This was paralleled by rescue of full BCR/Abl expression (Figure 2b). In this respect, it is worth pointing out that LC3 cells, when re-exposed to hypoxia, were as much hypoxia-sensitive as LC1 cells (data not shown). Thus, hypoxia/imatinib-resistant CRC eventually repopulate cultures with BCR/Abl-dependent, hypoxia/imatinib-sensitive cells. CRC, however, remains a minor, but constant, component of the population. Figure 2b also shows that full BCR/Abl expression was recovered at day 14 in imatinib-treated LC2 cells, while untreated LC2 cells required a further expansion in LC3. Thus, imatinib primed the hypoxia-resistant, BCR/Abl-independent cell subset to rescue BCR/Abl expression more rapidly once environmental conditions (normoxia) permissive for clonal expansion were restored. This is in keeping with the finding that the re-establishment of permissive conditions following imatinib removal determines BCR/Abl overexpression.6

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References

  1. Cipolleschi MG, Dello Sbarba P, Olivotto M . The role of hypoxia in the maintenance of hematopoietic stem cells. Blood 1993; 82: 2031–2037.

    CAS  Google Scholar 

  2. Cipolleschi MG, Rovida E, Ivanović Z, Praloran V, Olivotto M, Dello Sbarba P . The expansion of murine bone marrow cells preincubated in hypoxia as an in vitro indicator of their marrow-repopulating ability. Leukemia 2000; 14: 735–739.

    Article  CAS  Google Scholar 

  3. Ivanović Z, Belloc F, Faucher JL, Cipolleschi MG, Praloran V, Dello Sbarba P . Hypoxia maintains and interleukin-3 reduces the pre-colony-forming cell potential of dividing CD34(+) murine bone marrow cells. Exp Hematol 2002; 30: 67–73.

    Article  Google Scholar 

  4. Elrick LJ, Jorgensen HG, Mountford JC, Holyoake TL . Punish the parent not the progeny. Blood 2005; 105: 1862–1866.

    Article  CAS  Google Scholar 

  5. Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    Article  CAS  Google Scholar 

  6. Weisberg E, Griffin JD . Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000; 95: 3498–3505.

    CAS  Google Scholar 

  7. Desplat V, Belloc F, Lagarde V, Boyer C, Melo JV, Reiffers J et al. Overproduction of BCR-ABL induces apoptosis in imatinib mesylate-resistant cell lines. Cancer 2005; 103: 102–110.

    Article  CAS  Google Scholar 

  8. Jiang X, Ng E, Yip C, Eisterer W, Chalandon Y, Stuible M et al. Primitive interleukin-3-null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo. Blood 2002; 100: 3731–3740.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Istituto Superiore di Sanità (National Programme ‘Stem Cells’), Associazione Italiana per la lotta contro le Leucemie (AIL – Firenze), Ente Cassa di Risparmio di Firenze, Ministero della Università e della Ricerca.

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  1. Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Firenze, Italy

    S Giuntoli, E Rovida, V Barbetti, M G Cipolleschi, M Olivotto & P Dello Sbarba

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  1. S Giuntoli
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  2. E Rovida
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Giuntoli, S., Rovida, E., Barbetti, V. et al. Hypoxia suppresses BCR/Abl and selects imatinib-insensitive progenitors within clonal CML populations. Leukemia 20, 1291–1293 (2006). https://doi.org/10.1038/sj.leu.2404224

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