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Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia
Zhifu Xiang, … , Joseph T. Opferman, Michael H. Tomasson
Zhifu Xiang, … , Joseph T. Opferman, Michael H. Tomasson
Published May 17, 2010
Citation Information: J Clin Invest. 2010;120(6):2109-2118. https://doi.org/10.1172/JCI39964.
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Research Article Hematology Article has an altmetric score of 4

Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia

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Abstract

Antiapoptotic BCL2 family members have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (e.g., BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood. Here, we examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high levels in all samples tested. Consistent with this, Mcl1 protein was also highly expressed in myeloid leukemic blasts in a mouse Myc-induced model of AML. We used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade Myc-induced cell death. Indeed, activation of Myc for 7 days in vivo substantially increased myeloid lineage cell numbers, whereas hematopoietic stem, progenitor, and B-lineage cells were depleted. Furthermore, Mcl1 haploinsufficiency abrogated AML development. In addition, deletion of a single allele of Mcl1 from fully transformed AML cells substantially prolonged the survival of transplanted mice. Conversely, the rapid lethality of disease was restored by coexpression of Bcl2 and Myc in Mcl1-haploinsufficient cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients with de novo AML.

Authors

Zhifu Xiang, Hui Luo, Jacqueline E. Payton, Jennifer Cain, Timothy J. Ley, Joseph T. Opferman, Michael H. Tomasson

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Figure 3

Myc activation does not directly alter Mcl1 expression.

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Myc activation does not directly alter Mcl1 expression.
   
(A) Elevate...
(A) Elevated Myc target gene ODC expression upon Myc activation in 3T3 cells. RT-PCR was performed from RNA collected 0, 2, 4, and 6 hours after 4-OH tamoxifen treatment of MycER-transduced 3T3 cells (lanes 1–4, respectively) and GFP-transduced cells (0 and 6 hours; lanes 5 and 6, respectively). (B) Mcl1 expression was not changed in transduced BaF3 cells treated with ethanol (E) or with 4-OH tamoxifen dissolved in ethanol for the indicated times. SV40-transduced mouse embryonic fibroblasts (MEFs) were used as an Mcl1-positive control. (C) Mcl1 expression was not changed in transduced 3T3 cells treated for 24 hours with either 4-OH tamoxifen or ethanol. Myc-transduced 3T3 cells were used as a positive control. (D) Elevated Mcl1 expression in bone marrow cells after 7 days of Myc induction along with Gr-1+ cell expansion in bone marrow. Protein lysates were prepared from the mice treated with DMSO for 7 days (D7) or tamoxifen for 1 or 7days (T1 and T7, respectively). SV40-transduced mouse embryonic fibroblasts and bone marrow cells of Myc-induced leukemic mice were used as positive controls. Lanes were run on the same gel but were noncontiguous (white lines). (E) Tamoxifen treatment resulted in relative depletion of B220+ lymphoid cells with concurrent expansion of Gr-1+ myleoid cells in bone marrow (blue, Gr-1+; red, B220+). FSC, forward scatter; SSC, side scatter. Cells were gated for GFP, and the percentages of Gr-1+ and B220+ events are shown at right. Data are mean ± SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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