Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression

Mao, Guogen; Yuan, Fenghua; Absher, Kimberly J.; Jennings, C. Darrell; Howard, Dianna S.; Jordan, Craig T.; Gu, Liya

doi:10.1038/cr.2008.14

Cited by 35 publications

(28 citation statements)

References 37 publications

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“…These observations indicate that ATP hydrolysis by MutLα is essential for its ability to stimulate miRNA processing. This idea was further examined using MMR-deficient MutLα proteins MutLαEA, MutLαF99L and MutLαE705K [29,34,35]. Our results show that MutLαEA and MutLαF99L are proficient, but MutLαE705K is deficient in pri-miRNA binding ( Figure 4D).…”

Section: Guogen Mao Et Al 979mentioning

confidence: 83%

“…Our previous studies showed that a three-nucleotide deletion in the MLH1 3′-UTR is associated with leukemia relapse [12,29]. Computational analysis using MicroInspector [30] identified a putative binding site for miR-422a in the MLH1 3′-UTR that is disrupted by the 3-nucleotide deletion, suggesting a possible role for miR422a in regulating expression of MLH1.…”

Section: Mir-422a Regulates Mlh1 Expression By Interacting With the Mmentioning

confidence: 97%

“…As shown in Figure 4D, MutLα indeed specifically shifted 32 P-labeled pri-miR-422a even in the presence of excess, unlabeled competitor tRNA. Pri-miR-422a-binding reactions were also carried out with several MMR-deficient MutLα mutants, MutLαEA (MLH1 E34A -PMS2 E41A ) [33,34], MutLαF99L (MLH1 F99L -PMS2) [29] and MutLαE705K (MLH1-PMS2 E705K ) [35]. While MutLαEA ( Figure 4D, lanes 6-7) and MutLαF99L ( Figure 4D, lanes 8-9) bound pri-miR-422a as efficiently as the WT MutLα, MutLαE705K failed to interact with pri-miR-422a ( Figure 4D, lanes 10-11).…”

Section: Mutlα Interacts With Pri-mirna and Microprocessormentioning

confidence: 99%

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Modulation of microRNA processing by mismatch repair protein MutLα

et al. 2012

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MicroRNAs (miRNAs) are critical post-transcriptional regulators and are derived from hairpin-shaped primary transcripts via a series of processing steps. However, how the production of individual miRNAs is regulated remains largely unknown. Similarly, loss or overexpression of the key mismatch repair protein MutLα (MLH1-PMS2 heterodimer) leads to genome instability and tumorigenesis, but the mechanisms controlling MutLα expression are unknown. Here we demonstrate in vitro and in vivo that MLH1 and miR-422a participate in a feedback loop that regulates the level of both molecules. Using a defined in-vitro miRNA processing system, we show that MutLα stimulates the conversion of pri-miR-422a to pre-miR-422a, as well as the processing of other miRNAs tested, implicating MutLα as a general stimulating factor for miRNA biogenesis. This newly identified MutLα function requires its ATPase and pri-miRNA binding activities. In contrast, miR-422a downregulates MutLα levels by suppressing MLH1 expression through base pairing with the MLH1 3′-untranslated region. A model depicting this feedback mechanism is discussed.

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Section: Guogen Mao Et Al 979mentioning

confidence: 83%

Section: Mir-422a Regulates Mlh1 Expression By Interacting With the Mmentioning

confidence: 97%

Section: Mutlα Interacts With Pri-mirna and Microprocessormentioning

confidence: 99%

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Modulation of microRNA processing by mismatch repair protein MutLα

et al. 2012

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“…Although there are studies demonstrating increased rates of microsatellite instability in certain types of leukemia (mostly therapy-related AML and myelodysplastic syndromes (Ben-Yehuda et al 1996, Kaneko et al 1995), most reports have described little or no evidence of deficient MMR in AML (Boyer et al 1998, Sill et al 1996, Tasak et al 1996. However, while none of these studies focused on MMR deficiency in different stages of AML, in 2008 Mao et al showed that more than 30% of AML patients presented with mutations in MMR genes and that MMR deficiency was higher in patients with relapsed/ refractory AML (Mao et al 2008). Authors suggest the possibility of leukemia relapse generating from leukemic cells defective in MMR that have survived chemotherapy and present the minimal residual disease (Mao et al 2008).…”

Section: Dna Repair Deficiency Related To Hematological Malignanciesmentioning

confidence: 98%

“…However, while none of these studies focused on MMR deficiency in different stages of AML, in 2008 Mao et al showed that more than 30% of AML patients presented with mutations in MMR genes and that MMR deficiency was higher in patients with relapsed/ refractory AML (Mao et al 2008). Authors suggest the possibility of leukemia relapse generating from leukemic cells defective in MMR that have survived chemotherapy and present the minimal residual disease (Mao et al 2008). …”

Section: Dna Repair Deficiency Related To Hematological Malignanciesmentioning

confidence: 99%

DNA Repair Deficiency Associated with Hematological Neoplasms

Economopoulou¹,

Pappa²,

Papageorgiou³

et al. 2011

DNA Repair and Human Health

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Genetic instability in inherited and sporadic leukemias

Popp

Bohlander

2010

Genes Chromosomes & Cancer

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Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies.

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Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression

Cited by 35 publications

References 37 publications

Modulation of microRNA processing by mismatch repair protein MutLα

Modulation of microRNA processing by mismatch repair protein MutLα

DNA Repair Deficiency Associated with Hematological Neoplasms

Genetic instability in inherited and sporadic leukemias

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