Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute lymphoblastic leukemia (ALL) presenting with neutropenia alone is very rare. We describe a newborn with an early life-threatening infection, severe neutropenia and bone marrow findings compatible with severe congenital neutropenia (SCN). She was treated with granulocyte colony-stimulating factor (G-CSF) with complete neutrophil recovery. Three months later she developed a pro-B ALL. We identified a rare loss of 5'-MLL present at the diagnosis of SCN and ALL by FISH analysis using two different MLL (11q23) probes. Molecular analyses for SCN causing mutations (ELA-2, HAX-1 and G6PC3) and for somatic mutations of the CSF3R gene were negative. The early presence of 5'-MLL loss in bone marrow samples may favor the diagnosis of de novo ALL. Nevertheless, the genetic background for SCN is heterogeneous and a non-described mutation for SCN followed by a secondary ALL cannot be excluded. Further genetic investigation may be useful to gain insight into this rare condition in children.
 ...
PMID:Acute lymphoblastic leukemia following severe congenital neutropenia or de novo ALL? 1939 29

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.
 ...
PMID:[Classification of myeloid leukemias]. 1986 Jan 79

Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
 ...
PMID:The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. 2972 99