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MLL gene rearrangements have no direct impact on Ara-C sensitivity in infant acute lymphoblastic leukemia and childhood M4/M5 acute myeloid leukemia

Leukemia volume 20, pages 179–182 (2006)Cite this article

The antimetabolite cytosine arabinoside (Ara-C) is a deoxycytidine analog that is used as a therapeutic agent in many leukemia treatment regimens. In combination with anthracyclines, Ara-C is the most effective agent in the treatment of acute myeloid leukemia (AML). In the treatment of acute lymphoblastic leukemia (ALL), the use of Ara-C is limited. However, leukemic cells from infants (<1 year of age) with ALL, which are resistant to several chemotherapeutic drugs, are in vitro more sensitive to Ara-C as compared to older children with ALL.1, 2 This observation suggested that infant ALL might resemble a subclass of childhood ALL, which may benefit from intensified treatment with Ara-C to improve the dismal prognosis for these patients who to date experience an event-free survival (EFS) of ∼35%. Therefore, in 1999, a novel collaborative treatment protocol (INTERFANT-99) was designed with intensified use of Ara-C, in order to provide a more specific treatment to infant ALL patients.

Infant ALL is characterized by rearrangements of the Mixed Lineage Leukemia (MLL, ALL-1, or HRX) gene on chromosome band 11q23, in approximately 80% of the cases. The most common translocations involving MLL in infant ALL are t(4;11)(q21;q23) and t(11;19)(q23;p13.3) resulting in a fusion of MLL with AF-4 on chromosome 4 and ENL on chromosome 19, respectively. In childhood AML, MLL gene rearrangements are mainly restricted to the FAB M4 and M5 subtypes, and occur in the majority of the infant cases. Interestingly, childhood M4/M5 AML harboring t(9;11)(q22;q23) in which MLL is fused to AF-9 on chromosome 9 has also been reported to be highly sensitive to Ara-C when compared to other AML subtypes without MLL rearrangements.5 The fact that Ara-C sensitivity is found in both MLL rearranged infant ALL and MLL rearranged M4/M5 AML, raises an important question: is Ara-C sensitivity (or increased expression of ENT1) directly associated with rearrangements of the MLL gene? To answer this question, we set out to determine the relationship between Ara-C sensitivity, expression of Ara-C metabolizing enzymes, and the presence of MLL gene rearrangements in both infant ALL and pediatric AML M4/M5. Patient characteristics are listed in Table 1.

Table 1 Patient characteristics
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References

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Acknowledgements

We wish to express our gratitude to the members of the INTERFANT-99 study group, the AML-BFM study group, and the DCOG study group for their support to this study by providing fresh blood or bone marrow samples from newly diagnosed leukemia patients.

This study was financially supported by a Grant from the Sophia Foundation for Medical Research (SSWO Grant no. 296).

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Author notes

  1. R W Stam and I Hubeek: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands

    R W Stam, M L den Boer, J G C A M Buijs-Gladdines & R Pieters

  2. Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, The Netherlands

    I Hubeek & G J L Kaspers

  3. AML-BFM study group, Münster, Germany

    U Creutzig

  4. Interfant-99 Collaborative Study Group,

    R Pieters

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  1. R W Stam
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  2. I Hubeek
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  3. M L den Boer
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  4. J G C A M Buijs-Gladdines
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  6. G J L Kaspers
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Correspondence to M L den Boer.

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Stam, R., Hubeek, I., den Boer, M. et al. MLL gene rearrangements have no direct impact on Ara-C sensitivity in infant acute lymphoblastic leukemia and childhood M4/M5 acute myeloid leukemia. Leukemia 20, 179–182 (2006). https://doi.org/10.1038/sj.leu.2404031

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