scholarly journals Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation

2003 ◽  
Vol 23 (13) ◽  
pp. 4573-4585 ◽  
Author(s):  
Vernon T. Phan ◽  
David B. Shultz ◽  
Bao-Tran H. Truong ◽  
Timothy J. Blake ◽  
Anna L. Brown ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Cytokine Signaling ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Acute Myeloid

ABSTRACT We utilized a mouse model of acute promyelocytic leukemia (APL) to investigate how aberrant activation of cytokine signaling pathways interacts with chimeric transcription factors to generate acute myeloid leukemia. Expression in mice of the APL-associated fusion, PML-RARA, initially has only modest effects on myelopoiesis. Whereas treatment of control animals with interleukin-3 (IL-3) resulted in expanded myelopoiesis without a block in differentiation, PML-RARA abrogated differentiation that normally characterizes the response to IL-3. Retroviral transduction of bone marrow with an IL-3-expressing retrovirus revealed that IL-3 and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, βcV449E, cooperated with PML-RARα in leukemogenesis, whereas a different activated mutant, βcI374N, did not. Analysis of additional mutations introduced into βcV449E showed that, although tyrosine phosphorylation of βc is necessary for cooperation, the Src homology 2 domain-containing transforming protein binding site is dispensable. Our results indicate that chimeric transcription factors can block the differentiative effects of growth factors. This combination can be potently leukemogenic, but the particular manner in which these types of mutations interact determines the ability of such combinations to generate acute myeloid leukemia.

scholarly journals Acute Myeloid Leukemia Acquiring Promyelocytic Leukemia-Retinoic Acid Receptor Alpha at Relapse

2019 ◽  
Vol 10 (3) ◽  
pp. 153-156
Author(s):  
Varsha Gupta ◽  
Mohammed Shariff ◽  
Ravneet Bajwa ◽  
Ishan Patel ◽  
Hashem A. Ayyad ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Acute Myeloid

scholarly journals Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

2021 ◽  
Vol 12 ◽  
pp. 204062072097698
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Yi Li ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Specific Factor ◽  
Acid Receptor ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

scholarly journals ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3330-3338 ◽  
Author(s):  
Beatrice U. Mueller ◽  
Thomas Pabst ◽  
José Fos ◽  
Vibor Petkovic ◽  
Martin F. Fey ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
All Trans Retinoic Acid ◽  
Conditional Expression ◽  
Neutrophil Differentiation ◽  
Acute Myeloid

Abstract Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor α (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).

scholarly journals Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia

Leukemia ◽  
2006 ◽  
Vol 20 (3) ◽  
pp. 437-443 ◽  
Author(s):  
M Ritter ◽  
D Kattmann ◽  
S Teichler ◽  
O Hartmann ◽  
M K R Samuelsson ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Receptor Signaling ◽  
Acid Receptor ◽  
Acute Myeloid

scholarly journals Acute Promyelocytic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3718
Author(s):  
Xavier Thomas ◽  
Maël Heiblig
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Reciprocal Translocation ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Receptor Α ◽  
Distinct Subtype ◽  
Acute Myeloid

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor-α (RARα) [...]

scholarly journals A PML/retinoic acid receptor alpha fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3110-3115 ◽  
Author(s):  
S Castaigne ◽  
N Balitrand ◽  
H de The ◽  
A Dejean ◽  
L Degos ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Receptor Alpha ◽  
Rt Pcr ◽  
Amplification Product ◽  
Chain Reaction ◽  
Acid Receptor ◽  
Polymerase Chain

Abstract The t(15;17) translocation is specifically observed in patients with promyelocytic leukemia (AML3). The chromosomal rearrangement juxtaposes the retinoic acid receptor alpha (RAR alpha) and PML genes, resulting in PML/RAR alpha fusion transcripts. Our previous studies have shown that a polymerase chain reaction (PCR) amplification product could be obtained from the cDNA of the NB4 promyelocytic cell line from which the chimaeric PML/RAR alpha was cloned. We report here that in all 14 AML3 patients tested, reverse transcriptase-PCR (RT-PCR) allows the detection of three specific fusion products. In eight patients, one amplification product was detected corresponding to the previously described abnormal fusion. Five patients displayed a different amplified fragment corresponding to a different fusion point. One other patient always showed a third different-sized product. The different types of fusion transcripts amplified were correlated to the size of the abnormal RAR alpha transcripts detected in these patients by Northern analysis, but did not prove determinant for either the phenotypic features or the retinoic acid responsiveness in AML3 cells in this group of patients. The consistent identification by RT-PCR of the fusion of the PML and RAR alpha genes in AML3 patients suggest that this method will provide a useful tool for the diagnosis and detection of minimal residual disease in these patients.

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