The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.
Recently, constitutively activated Stat1, Stat3, and Stat5 were identified in nuclear extracts of acute myeloid leukemia (AML) patients, suggesting involvement of constitutive Stat activity in the events of leukemogenesis.
TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized.
To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed.
Collectively, our data suggest that PBX3 is a critical cofactor of HOXA9 in leukemogenesis, and targeting their interaction is a feasible strategy to treat presently therapy resistant CA-AML (eg, MLL-rearranged leukemia) in which HOXA/PBX3 genes are overexpressed.
These findings suggest that the basis for the leukemogenesis of t(11; 22)-AML is the inability of p300 to regulate cell-cycle and cell differentiation after fusion with MLL.
The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase β (GSK3β) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma.
Recent studies have shown that miR-17-92 down-regulates the proapoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis.
The 2016 WHO classification defines diffuse large B-cell lymphoma subtypes based on EBV infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis.
Activating mutations of FLT3 are present in approximately one-third of patients, while many nonmutants show evidence of FLT3 activation, which appears to play a significant role in leukemogenesis.
These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins.
Because DLCL derive from germinal-center B cells, deregulated BCL-6 expression may contribute to lymphomagenesis by preventing postgerminal center differentiation.
AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis.
Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis.
Thus, AML-1-ETO may contribute to leukemogenesis by specifically inhibiting C/EBP-alpha- and AML-1B-dependent activation of myeloid promoters and blocking differentiation.
Here we show that while the X-RARalpha fusion gene is crucial for leukemogenesis, the presence of RARalpha-X and the inactivation of X function are critical in modulating the onset as well as the phenotype of the leukemia.
In this review, we survey recent advances made involving secondary mutational events and alternative t(8;21) transcripts in relation to understanding AML1-ETOleukemogenesis.
Our results indicate that the production of chimeric AML1-MTG8 protein, probably a chimeric transcription factor, may contribute to myeloid leukemogenesis.
This review focuses on the molecular mechanisms underlying MLL1 translocation-driven leukemogenesis and the latest progress on DOT1L-targeted epigenetic therapies for MLL1-rearranged and other leukemias.