11q23/MLL Acute Leukemia : Update of Clinical Aspects

Tamai, Hayato; Inokuchi, Koiti

doi:10.3960/jslrt.50.91

Cited by 60 publications

(45 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The one following The partner gene t (11;19) seen in our patient constitutes 5 % of the 11q23 rearrangements. Childhood AML with this translocation has an intermediate prognosis [4].…”

Section: Discussionmentioning

confidence: 99%

Concurrent Presentation of Therapy Related Acute Myeloid Leukemia in a Case of Neuroblastoma

Sylvia

Rani

Basu

et al. 2015

Indian J Hematol Blood Transfus

View full text Add to dashboard Cite

Therapy related Acute Myeloid Leukemia/ Myelodysplastic syndrome (t-AML/MDS) occur due to the direct mutational events of the chemotherapeutic agents and radiotherapy. The disease latency, mutational events and prognosis vary with the type of chemotherapeutic agent. Therapy related Acute Myeloid Leukemia occurring with DNA topoisomerase II inhibitors have a shorter latency period and poor prognosis than anthracyclin based regimens. We report a case of a 9 year old boy who developed t-AML with mixed-lineage-leukemia gene translocation within a year of high dose chemotherapy for stage 4 neuroblastoma. He had residual mass of neuroblastoma in the abdomen and bone marrow. The patient expired within 2 weeks of induction chemotherapy.

show abstract

“…The one following The partner gene t (11;19) seen in our patient constitutes 5 % of the 11q23 rearrangements. Childhood AML with this translocation has an intermediate prognosis [4].…”

Section: Discussionmentioning

confidence: 99%

Concurrent Presentation of Therapy Related Acute Myeloid Leukemia in a Case of Neuroblastoma

Sylvia

Rani

Basu

et al. 2015

Indian J Hematol Blood Transfus

View full text Add to dashboard Cite

show abstract

“…[12][13][14] Moreover, rearrangements involving the MLL locus are frequent in human AML. 15 Myb was shown to mediate the activity of MLL-AF9 in leukemia self-renewal. 16 In our studies, we sought to decipher the NRAS functions critical for tumor maintenance in AML.…”

Section: G12vmentioning

confidence: 99%

NRAS G12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia

Sachs¹,

LaRue

Nguyen³

et al. 2014

Blood

View full text Add to dashboard Cite

Key Points• NRAS G12V maintains leukemia self-renewal in a genetically engineered murine model of AML.• NRAS G12V differentially regulates transcription and signaling among leukemic subpopulations.Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS G12V ). Using computational approaches to explore our gene-expression data sets, we found that NRAS G12V enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9-and Myb-dependent leukemia self-renewal geneexpression program. NRAS G12V was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS G12V -mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1 Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS G12V withdrawal. NRAS G12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction. (Blood. 2014;124(22):3274-3283)

show abstract

“…[1][2][3][4] Acute leukemias bearing MLL rearrangements are aggressive diseases. Current treatment options are limited to chemotherapy and allogeneic hematopoietic stem cell transplantation; however, these have significant side effects and outcomes remain poor.…”

Section: Introductionmentioning

confidence: 99%

“…2013;122(6):1017-1025 Introduction Rearrangements in the MLL gene at position 11q23 occur in 5% to 10% of acute leukemias of lymphoid, myeloid, or mixed/ indeterminant lineage and are especially common in infant acute leukemias and in secondary acute myeloid leukemias arising in patients following treatment of other malignancies with topoisomerase II inhibitors. [1][2][3][4] Acute leukemias bearing MLL rearrangements are aggressive diseases. Current treatment options are limited to chemotherapy and allogeneic hematopoietic stem cell transplantation; however, these have significant side effects and outcomes remain poor.…”

mentioning

confidence: 99%

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia

Daigle

Olhava

Therkelsen

et al. 2013

Blood

637

599

View full text Add to dashboard Cite

• EPZ-5676 is a potent DOT1Linhibitor that causes tumor regressions in a rat xenograft model of MLL-rearranged leukemia.Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation. (Blood. 2013;122(6):1017-1025 Introduction Rearrangements in the MLL gene at position 11q23 occur in 5% to 10% of acute leukemias of lymphoid, myeloid, or mixed/ indeterminant lineage and are especially common in infant acute leukemias and in secondary acute myeloid leukemias arising in patients following treatment of other malignancies with topoisomerase II inhibitors. [1][2][3][4] Acute leukemias bearing MLL rearrangements are aggressive diseases. Current treatment options are limited to chemotherapy and allogeneic hematopoietic stem cell transplantation; however, these have significant side effects and outcomes remain poor. As a result, there is intense interest in developing novel therapeutic strategies for this disease. The MLL gene encodes a large multidomain protein (MLL) that regulates transcription of developmental genes including the HOX genes. 1 The amino terminal portion of the protein contains regions that target MLL to DNA directly, whereas the carboxyl terminal portion of the protein contains a Su(Var)3-9, Enhancer of zeste and Trithorax domain with methyltransferase activity specific for lysine 4 of histone H3 (H3K4).5-9 MLL rearrangements result in the loss of the carboxyterminal methyltransferase domain and an in-frame fusion of the amino-terminal region of MLL to 1 of more than 60 potential fusion partners. [1][2][3] The vast majority of translocations result in oncogenic fusion proteins in which the native methyltransferase domain is replaced by sequences derived from AF4, AF9, AF10, and ENL, which interact with DOT1L directly or indirectly in complexes that promote transcriptional elongation.10-18 DOT1L is a histone methyltransferase enz...

show abstract

11q23/MLL Acute Leukemia : Update of Clinical Aspects

Cited by 60 publications

References 41 publications

Concurrent Presentation of Therapy Related Acute Myeloid Leukemia in a Case of Neuroblastoma

Concurrent Presentation of Therapy Related Acute Myeloid Leukemia in a Case of Neuroblastoma

NRAS G12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia

Contact Info

Product

Resources

About