Acute promyelocytic leukemia pathophysiology

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

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. 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). 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.
• 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.
• 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.

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	Most common translocation Found in 70-90% of cases
PLZF (ZBTB16)	11q23.2	Encodes a zinc finger transcription factor Involved in cell cycle regulation Interacts with histone deacetylases	Resistant to all-trans retinoic acid	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	NPM1 mutation carries a favorable prognosis in acute myeloid leukemia Rare translocation
NUMA	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	Rare translocation
STAT5B	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	Rare translocation