Reproductive Disorders Associated with Pesticide Exposure
Ana Maria Osorio, Lynn R. Goldman in Proceedings from the Medical Workshop on Pesticide-Related Illnesses from the International Conference on Pesticide Exposure and Health, 2017
Childhood Cancer: Exposure to indoor pesticides during pregnancy doubled the risk for childhood leukemia in a well-designed case-control study in California.58 At the time of the study, the most common home insecticides used in the region were chlorpyrifos, piperonyl butoxide, pyrethrins and propoxur. In a study of 136 cases of infant leukemia and 266 controls, having an affected child was associated with maternal exposure to pesticides during pregnancy, particularly the carbamate, propoxur.59 The finding was most striking among infants with cleavage of the mixed lineage leukemia (MLL) gene, which is a known mechanism of leukemia induction after treatment with anti-neoplastic drugs or radiation. A case of infant leukemia with MLL gene rearrangement has also been reported after intensive exposure to permethrin during pregnancy.60
B-Lymphoblastic Leukemia/Lymphoma
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Rearrangements of the mixed-lineage leukemia gene MLL (also known as ALL1, Htrx, HRX) on 11q23 are associated with aggressive acute leukemias and poor prognosis in both children and adults. This type is most common in children <1 year old. The MLL gene can undergo rearrangements with over 100 partners, the most common being t(4;11)(q21;q23)/MLL–AFF1, and t(11;19)(q23;p13.3)/MLL–ENL. The other less common fusions include t(9;11)(p211;q23)/MLL–AF9, t(6;11)(q27;q23)/MLL–AF6, and t(10;11)(p12–14;q23)/MLL–AF10. The MLL translocations are most common among infants (70%–80%), the incidence among children decreases to 2%–3%, and then the t(4;11) gradually increases in adults. Infants with translocation involving 11q23 present with a high WBC count, an increased frequency of CNS involvement, and a very poor prognosis (they are classified as high-risk disease). Patients with t(4;11) B-ALL have poor prognosis at all ages. Some of the MLL rearrangements, such as t(11;19), can occur in T-ALL.
Practical Approach to Molecular Biology in Hematopathology
Harold R. Schumacher, William A. Rock, Sanford A. Stass in Handbook of Hematologic Pathology, 2019
Reverse transcriptase (RT) PCR assays have been developed to detect the t(l5;l7)-encoded PML-RARa, the t(8;21)-encoded AMLI-ETO, the inv(16) CBFß-MYHII, and the most prevalent translocations affecting the MLL gene. Each of these assays allows the rapid and specific detection of the molecular lesions; moreover, RT-PCR assays provide an exceptional level of one leukemic cell among 106 normal cells, permitting one to monitor a patient’s response to therapy. Detection of the presence of minimal residual disease (MRD) in a patient following documented molecular remission is strongly correlated with impending relapse in cases of t(15; 17)-containing APL. Similarly, evidence of MRD in leukemia with MLL rearrangements id predicative of imminent relapse. By contrast, persistent molecular transcripts have been observed in patients in long-term remission. The significance of the positive result in these patients remains to be defined. The possibility exists that these patients have a persistent clone containing the translocation responsible for generating the AML1 or CBFß chimeric protein, but lack the cooperating mutations necessary for the development of the full leukemic phenotype. This possibility is supported recent data obtained from expression of these fusion proteins in murine experimental systems. Thus, the data suggest that these patients have a preleukemic clone incapable of producing leukemia. Treatment of these patients at this point in time may be ill advised, in that it might not eradicate the clonal population, but instead my induce secondary mutations that could result in full conversion to a leukemic phenotype (52–55, 57).
Menin-MLL protein-protein interaction inhibitors: a patent review (2014–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Huanrong Bai, San-Qi Zhang, Hao Lei, Fang Wang, Mengyan Ma, Minhang Xin
The mixed lineage leukemia (MLL, also known as KMT2A, MLL1) protein is a kind of histone methyltransferases, which is targeted by chromosomal translocations and rearrangements in the acute leukemia (AL) observed in approximately 10% of human leukemia patients [1–3]. The oncogenic activity of MLL fusion proteins depends on the direct interaction with the Menin protein, which is a tumor suppressor controlling the cellular growth in the endocrine organs [4–6]. Studies have shown that the binding of Menin to the N-terminal motif of the MLL fusion protein is essential for MLL fusion acute leukemia [7–9]. Therefore, inhibition of the Menin-MLL protein-protein interactions is considered as a therapeutic strategy for relapsed or refractory AL, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and phenotypic leukemia.
Proteomic approaches for cancer epigenetics research
Published in Expert Review of Proteomics, 2019
Dylan M. Marchione, Benjamin A. Garcia, John Wojcik
MLL is a histone H3K4 methyltransferase [91,92]. Over 70% of pediatric leukemias and approximately 10% of adult leukemias bear a translocation involving the MLL gene [93]. These translocations typically create fusion genes in which the 5ʹ portion of MLL is fused to the 3ʹ portion of another gene, deleting its methyltransferase (SET) domain but retaining several DNA-binding domains. Over 135 translocation partner genes (TPGs) have been described to date, but a few TPGs account for approximately 90% of MLL translocations. These are: ENL, ELL, AF4, AF6, AF9, and AF10 [94,95]. Thus, MLL fusion partners are not random, they instead appear to be strongly selected for based upon their function. Affinity proteomic characterizations of wild-type MLL, several of its fusion partners, and of chimeric MLL proteins have enabled detailed characterization of how this conversion occurs. For additional reading on the fascinating genetics of MLL fusions, we recommend the following reviews [93,96,97].
MLLT10 promotes tumor migration, invasion, and metastasis in human colorectal cancer
Published in Scandinavian Journal of Gastroenterology, 2018
Xiaoqian Jing, Haoxuan Wu, Xi Cheng, Xianze Chen, Yaqi Zhang, Minmin Shi, Tao Zhang, Xiongjun Wang, Ren Zhao
Mixed lineage leukemia (MLL), a crucial controller of hematopoiesis, encodes a highly conserved transcription factor being a part of the Trithorax family of transcriptional activators [4]. MLL is also a regulator of homeotic genes (Hox genes) and is associated with the development of leukemia [5–8]. MLLT10, also known as AF10, is located at 10p12. As a recurrent MLL partner, AF10 participates in translocation with the clathrin-assembly lymphoid–myeloid (CALM) gene [9,10]. Recent studies have shown that the translocations t(10;11)(p12;q23) and t(10;11)(p12;q14), which result in MLL-AF10 and CALM-AF10 fusion proteins, are almost exclusively found in patients with acute myeloid or acute lymphoid leukemia [11,12]. Molecular analyses of MLL- and CALM-AF10 rearrangements demonstrate differences in the location of MLLT10 breakpoints [13].
Related Knowledge Centers
- Enzyme
- Epigenetics
- Haematopoiesis
- Methyltransferase
- Transactivation
- Chromatin
- Gene
- Transcription
- Histone-Modifying Enzymes
- Set Domain