Acute promyelocytic leukemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

Overview

The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

Pathophysiology

The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.^[1]
The chromosomal translocation involves the juxtaposition of the retinoic acid receptor– alpha gene (RARA) on the long arm of chromosome 17 with another gene, most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15. The translocation is designated as t(15;17)(q22;q12).^[2]^[3]
The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome.
The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.^[4]^[5]
This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The cells remain primitive and stem-like, which is the basis for the malignancy. The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.^[2]
In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.^[6]


Translocation Partner	Chromosomal Location	Function	Response to Therapy	Other Features

PML	15q24.1	A member of the tripartite motif (TRIM) family Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor Regulate p53 response to oncogenic growth signals Influenced by the cell cycle	Sensitive to all-trans retinoic acid^[7]	Most common translocation Found in 70-90% of cases^[8]
PLZF (ZBTB16)^[2]^[8]	11q23.2	Encodes a zinc finger transcription factor Involved in cell cycle regulation Interacts with histone deacetylases	Resistant to all-trans retinoic acid^[7]	Second most common translocation (after PML-RARA)
NPM1	5q35.1	Encodes nucleophosmin 1 (a nucleolar shuttle protein) Involved in centromere duplication Serves a protein chaperone Regulates the cell cycle Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation	Sensitive to all-trans retinoic acid^[7]	NPM1 mutation carries a favorable prognosis in acute myeloid leukemia Rare translocation
NUMA^[7]	11q13.4	Contributes to a structural component of the nuclear matrix Interacts with microtubules Contributes to mitotic spindle formation during cell division	Sensitive to all-trans retinoic acid^[7]	Rare translocation
STAT5B^[8]	17q21.2	Encodes a signal transducer and activator of transcription (STAT) Serves an intracellular transduction molecule for cytokine signaling Translocates to the nucleus and functions as a transcription factor Involved in T cell receptor signaling Involved in apoptosis Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation	Resistant to all-trans retinoic acid^[7]	Rare translocation

References

↑ Zelent, Arthur; Guidez, Fabien; Melnick, Ari; Waxman, Samuel; Licht, Jonathan D (2001). “Translocations of the RARα gene in acute promyelocytic leukemia”. Oncogene. 20 (49): 7186–7203. doi:10.1038/sj.onc.1204766. ISSN 0950-9232.
↑ ^2.0 ^2.1 ^2.2 Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A (2017). “Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia”. Case Rep Hematol. 2017: 7657393. doi:10.1155/2017/7657393. PMC 5424191. PMID 28529810.
↑ L. R. Hiorns, T. Min, G. J. Swansbury, A. Zelent, M. J. Dyer & D. Catovsky (1994). “Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17”. Blood. 83 (10): 2946–2951. PMID 8180390. Unknown parameter |month= ignored (help)
↑ Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). “The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy”. Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.
↑ “RARA retinoic acid receptor alpha [Homo sapiens (human)] – Gene – NCBI”.
↑ Saeed, S; Logie, C; Stunnenberg, H G; Martens, J H A (2011). “Genome-wide functions of PML–RARα in acute promyelocytic leukaemia”. British Journal of Cancer. 104 (4): 554–558. doi:10.1038/sj.bjc.6606095. ISSN 0007-0920.
↑ ^7.0 ^7.1 ^7.2 ^7.3 ^7.4 ^7.5 Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). “Emerging new approaches for the treatment of acute promyelocytic leukemia”. Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.
↑ ^8.0 ^8.1 ^8.2 Chen C, Huang X, Wang K, Chen K, Gao D, Qian S (2018). “Early mortality in acute promyelocytic leukemia: Potential predictors”. Oncol Lett. 15 (4): 4061–4069. doi:10.3892/ol.2018.7854. PMC 5835847. PMID 29541170.

Template:WH Template:WS

[ZelentGuidez2001-1] Zelent, Arthur; Guidez, Fabien; Melnick, Ari; Waxman, Samuel; Licht, Jonathan D (2001). “Translocations of the RARα gene in acute promyelocytic leukemia”. Oncogene. 20 (49): 7186–7203. doi:10.1038/sj.onc.1204766. ISSN 0950-9232.

[pmid28529810-2] 2.0 ^2.1 ^2.2 Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A (2017). “Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia”. Case Rep Hematol. 2017: 7657393. doi:10.1155/2017/7657393. PMC 5424191. PMID 28529810.

[3] L. R. Hiorns, T. Min, G. J. Swansbury, A. Zelent, M. J. Dyer & D. Catovsky (1994). “Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17”. Blood. 83 (10): 2946–2951. PMID 8180390. Unknown parameter |month= ignored (help)

[pmid26716387-4] Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). “The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy”. Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.

[urlRARA_retinoic_acid_receptor_alpha_[Homo_sapiens_(human)]_-_Gene_-_NCBI-5] “RARA retinoic acid receptor alpha [Homo sapiens (human)] – Gene – NCBI”.

[SaeedLogie2011-6] Saeed, S; Logie, C; Stunnenberg, H G; Martens, J H A (2011). “Genome-wide functions of PML–RARα in acute promyelocytic leukaemia”. British Journal of Cancer. 104 (4): 554–558. doi:10.1038/sj.bjc.6606095. ISSN 0007-0920.

[pmid23556100-7] 7.0 ^7.1 ^7.2 ^7.3 ^7.4 ^7.5 Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). “Emerging new approaches for the treatment of acute promyelocytic leukemia”. Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.

[pmid29541170-8] 8.0 ^8.1 ^8.2 Chen C, Huang X, Wang K, Chen K, Gao D, Qian S (2018). “Early mortality in acute promyelocytic leukemia: Potential predictors”. Oncol Lett. 15 (4): 4061–4069. doi:10.3892/ol.2018.7854. PMC 5835847. PMID 29541170.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]