As the transcriptional coactivator CITED2 (CBP/p300-interacting-transactivator-with-an ED-rich-tail 2) can be overexpressed in acute myeloid leukemia (AML) cells, we analyzed the consequences of high CITED2 expression in normal and AML cells. CITED2 overexpression in normal CD34(+) cells resulted in enhanced hematopoietic stem and progenitor cell (HSPC) output in vitro, as well as in better hematopoietic stem cell (HSC) engraftability in NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice. This was because of an enhanced quiescence and maintenance of CD34(+)CD38(-) HSCs, due in part to an increased expression of the cyclin-dependent kinase inhibitor CDKN1A. We demonstrated that PU.1 is a critical regulator of CITED2, as PU.1 repressed CITED2 expression in a DNA methyltransferase 3A/B (DNMT3A/B)-dependent manner in normal CD34(+) cells. CD34(+) cells from a subset of AML patients displayed higher expression levels of CITED2 as compared with normal CD34(+) HSPCs, and knockdown of CITED2 in AML CD34(+) cells led to a loss of long-term expansion, both in vitro and in vivo. The higher CITED2 expression resulted from reduced PU.1 activity and/or dysfunction of mutated DNMT3A/B. Collectively, our data demonstrate that increased CITED2 expression results in better HSC maintenance. In concert with low PU.1 levels, this could result in a perturbed myeloid differentiation program that contributes to leukemia maintenance.

polymerase in the process of PCR amplification, releasing the reporter dyes. Following PCR, plates were read using the 7900HT Fast Real-Time PCR system, and the data were analyzed using Allele Discrimination software (Applied Biosystems).The median age at multiple myeloma diagnosis was 66 years and the median year of diagnosis was 1992 (Table 1). For multiple myeloma patients who subsequently developed MDS, in accord with prior studies, 9 the median time between the two diagnoses was 3.9 years (range: 1.8-14.3). When we assessed the results from the genotyping, we found 4 out of 15 (27%) of the multiple myeloma patients who developed MDS had the G/G genotype, whereas only 2 out of 17 (12%) of the patients who did not develop MDS showed the G/G genotype. The G/T genotype was found in 47% of both groups; multiple myeloma patients who did not develop MDS had a higher fraction of T/T genotype (41% vs 27%).Our novel findings support a role for susceptibility genes in the development of second malignancies following the diagnosis of multiple myeloma, likely in combination with multiple myeloma therapies. Future studies are needed to replicate and expand on our observations, with the overall goal of characterizing the role for treatment-and nontreatmentrelated factors underlying the development of secondary malignancies subsequent to multiple myeloma. Conflict of interestThe authors declare no conflict of interest. AcknowledgementsThe study was approved by the Mayo Clinic Institutional Review Board; informed consent was obtained from all participants in this study. An exemption from institutional review board review was obtained from the National Institutes of Health Office of Human Subjects Research because we used anonymous data/samples. Letters to the Editor 845Leukemia susceptible to the cytotoxic actions of these drugs.1 Therefore, interfering with the cholesterol metabolism by using statins to suppress cholesterol synthesis has been proposed as a method to improve antileukemic treatment strategies.3 Statins (for example, simvastatin) are widely used plasma cholesterol-lowering drugs that inhibit cholesterol synthesis at the level of HMG-CoA reductase (HMG-CoAR) by blocking the conversion of HMG-CoA to mevalonate. Mevalonate is also the precursor of isoprenoids such as farnesyldiphosphate (FPP) and geranylgeranyldiphosphate (GGPP). Isoprenylation, catalyzed by farnesyltransferase or geranylgeranyltransferase, is required for the attachment of small GTPases (for example, Rho, Ras) to the plasma membrane and their subsequent participation in signal transduction pathways that regulate growth and survival. Statins induce cell death in various human AML cell lines, as well as in primary human AML cells in vitro.1,4 Different mechanisms of action have been proposed for simvastatinmediated cell death, including the direct consequences of suppressed cholesterol synthesis and inhibition of isoprenylation and thereby the actions of signaling molecules such as Ras. 1,5 Ras is frequently activated in AML cells by mutatio...

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