We model calreticulin (CALR) mutations in murine interleukin-3 (mIL-3) dependent pro-B (Ba/F3) cells by delivery of single guide RNAs (sgRNAs) targeting the endogenous Calr locus in the specific region where insertion and/or deletion (indel) CALR mutations occur in patients with myeloproliferative neoplasms (MPN), a type of blood cancer.
CBL linker region and RING finger mutations lead to enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via elevated levels of JAK2 and LYN.
We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML.
With the discoveries of underlying mutations in JAK2, MPL, and, most recently, calreticulin (CALR), that together account for ∼90% of patients with MPNs, these conditions are now among the best characterized of hematological malignancies.
Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies.
The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved.We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors.We report one IDH1 variant: c.315 G>T, p.Gly105Gly in 15 % of cases, which was assigned to the worst outcome in several studies.
Prospective phase I, II, and III clinical trials using reversing agents in conjunction with chemotherapy in malignancies that express the MDR1 gene, such as the hematologic malignancies and breast cancer, are necessary before routine use of agents such as verapamil, quinidine, and cyclosporine, which carry innate toxicities.
Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma.
The mutations of isocitrate dehydrogenase 1 (IDH1) gene have been identified in a proportion of hematologic malignancies including acute myeloid leukemia (AML).
From a phase 1 study of 258 patients with IDH1-mutant advanced hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received ivosidenib 500 mg once daily.
Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma.
The importance of the TET-mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (IDH1) and IDH2 in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2-hydroxyglutarate.
Moreover, overexpression of the MDR1 gene has been shown to be associated closely with clinical outcome in various hematological malignancies, including acute myeloid leukemia (AML).
Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma.
Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies.
These findings supported initiation of the ongoing clinical trials of AG-221 in patients with <i>IDH2</i> mutation-positive advanced hematologic malignancies.<b>Significance:</b> Mutations in <i>IDH1/2</i> are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation.
We here summarize the basic physiology of IDH, the metabolic and oncogenic consequences of mutant IDH1/2, and the clinical significance of IDH inhibition in hematologic malignancies.
Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma.