Journal article
Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia
The Journal of clinical investigation, Vol.120(6), pp.2109-2118
06/01/2010
DOI: 10.1172/JCI39964
PMCID: PMC2877934
PMID: 20484815
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.
Details
- Title: Subtitle
- Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia
- Creators
- Zhifu Xiang - Department of Medicine, Division of Oncology, andHui Luo - Department of Medicine, Division of Oncology, andJacqueline E Payton - Department of Medicine, Division of Oncology, andJennifer Cain - Department of Medicine, Division of Oncology, andTimothy J Ley - Department of Medicine, Division of Oncology, andJoseph T Opferman - Department of Medicine, Division of Oncology, andMichael H Tomasson - Department of Medicine, Division of Oncology, and
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.120(6), pp.2109-2118
- DOI
- 10.1172/JCI39964
- PMID
- 20484815
- PMCID
- PMC2877934
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 06/01/2010
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094504402771
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