Leukemic transformation with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 chromosomal translocation from JAK2-mutated myeloproliferative neoplasms

Yuichi Nakamura¹

¹Department of Hematology, Saitama Medical University Hospital, Moroyama, Saitama, Japan

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Abstract

Background: Leukemic transformation is a rare, but well-recognized event in Philadelphia (BCR::ABL1)-negative myeloproliferative neoplasms (MPNs) and is associated with a poor prognosis. Secondary acute myeloid leukemia (AML) arising from MPNs is characterized by a unique set of morphological, cytogenetic, and molecular features distinct from de novo disease. Balanced chromosomal translocations, such as t(8;21), inv(16)/t(16;16), and t(15;17), frequently observed in de novo AML with favorable-risk cytogenetics, are quite rare in post-MPN AML.

Objective: We and others have recently reported two cases of AML with t(8;21)(q22;q22.1);RUNX1::RUNX1T1 arising from JAK2V617F-mutated essential thrombocythemia and polycythemia vera. This mini-review summarizes the features and possible biological cooperation between t(8;21) and JAK2V617F in hematologic malignancies.

Conclusions: Both cases were thought to have evolved from JAK2-mutated MPN clones, indicating that t(8;21) can occur as a late event in MPN progression. The accumulation of such cases and further mechanistic investigations will be useful for understanding leukemic transformation in MPNs.

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Introduction

Philadelphia (Ph) or BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the proliferation of mature blood cells. Among these, polycythemia vera (PV) and essential thrombocythemia (ET) are the most common entities associated with chronic and indolent clinical courses. Activating mutations in the JAK/STAT signaling pathway, primarily JAK2, MPL, and CALR, proposed as “disease driver” mutations, are present in most patients, exerting a primary pathogenetic role that leads to blood cell proliferation.¹ In addition, epigenetic modification genes such as TET2, DNMT3A, ASXL1, and EZH2 are also commonly mutated in MPNs with a frequency of 3–50%.^1–3 These mutations are proposed as “clonal driver” mutations and may lead to clonal hematopoiesis of indeterminate potential (CHIP) prior to MPN onset.¹

Leukemic transformation is a rare, but well-recognized event in Ph-negative MPNs, and is associated with a poor prognosis.^1–3 Secondary acute myeloid leukemia (AML) arising from MPNs is characterized by a unique set of cytogenetic and molecular features distinct from those of de novo AML.^1–5 Somatic mutations in TP53, ASXL1, IDH1/2, TET2, and RUNX1 genes occur more frequently in post-MPN AML than in de novo disease.^1–5 By contrast, balanced or reciprocal chromosomal translocations such as t(8;21)(q22;q22.1), inv(16)(p13.1q22)/t(16;16)(p13.1;q22), and t(15;17)(q22;q11-12), which are the most common cytogenetic aberrations in de novo AML, are rare in post-MPN AML.^6–18 This suggests a disparate pathway for leukemogenesis.

Recently, we and others reported two cases of AML with t(8;21)/RUNX1::RUNX1T1 arising from JAK2V617F-mutated ET⁸ and PV.⁹ Based on these observations, this mini-review summarizes the features of leukemia presenting with the coexistence of JAK2 mutation and t(8;21) translocation.

Leukemic Transformation of MPNs

Leukemic transformation is an end-stage event in the natural history of MPNs. The risk of leukemic progression varies according to the clinical features at the time of MPN diagnosis, with the transformation risk being the highest in primary myelofibrosis, estimated as a 10-year risk of 10–20%, followed by PV (2–4%) and ET (1–2%).²

Secondary AML arising from MPNs is characterized by a unique set of morphological, cytogenetic, and molecular features distinct from those of de novo AML, suggesting a disparate path to leukemogenesis. Post-MPN AML often displays an inordinately high rate of erythroblastic and megakaryoblastic morphology.¹⁹ An in vivo murine model demonstrated that combined expression of JAK2V617F and TP53 loss resulted in fully penetrant AML characterized by an expanded megakaryocyte-erythroid progenitor population.⁴

Although specific cytogenetic aberrations in post-MPN AML have not been identified, chromosomal karyotyping in chronic-phase MPN remains one of the most important predictors of leukemic progression. Chromosomal alterations associated with poor-risk outcomes in MPNs include complex karyotypes (≥3 cytogenetic abnormalities), any combination of more than one of i(17q), −5/5q−, −7/7q−, +8, 12p−, inv(3) or 11q23 rearrangements, monosomal karyotype (≥2 autosomal monosomies or one monosomy plus any other cytogenetic abnormality), or chromosome 17p deletion.²

Recent studies have clarified the frequent occurrence of additional somatic alterations beyond disease driver mutations in MPNs.^1–5 Genomic profiling revealed a recurring set of specific mutations enriched at the time of leukemic transformation, suggesting potential roles in leukemogenesis^1–5 (Table 1). These included mutations in TP53, TET2, DNMT3A, ASXL1, RUNX1, IDH1/2, and RAS family genes. A comparison of de novo AML and post-MPN AML revealed that the frequency of somatic mutations commonly implicated in de novo disease, such as FLT3, NPM1, CEBPA, and WT1, was extremely low in post-MPN AML, whereas IDH1/2, TET2, ASXL1, EZH2, SRSF2, and TP53 were mutated at higher rates, implying a distinct molecular pathogenesis.^1–3

In MPNs, constitutive activation of the JAK/STAT system by disease driver mutations occurs from the early stage of disease, and additional mutations of various functions, such as epigenetic modification, RNA splicing, transcription, and signal transduction, promote disease progression.^1–5 Epigenetic changes may induce further transformation by modification of the tumor microenvironment, such as reduction of antitumor immunity and enhancement of angiogenesis, by additional activation of signal transduction systems, as reported in other neoplasms.^20,21

Clonality analysis revealed that JAK2V617F is not always an initiating mutation and can occur as a secondary event. Mutations in the epigenetic modifiers TET2 and DNMT3A most commonly occur, inducing a CHIP state, before the acquisition of JAK2V617F, whereas mutations in IDH1/2 generally occur after JAK2.² It has been hypothesized that an earlier somatic event, such as mutation of ASXL1, TET2, or SRSF2, confers susceptibility to the acquisition of additional mutations, including JAK2.² However, TET2 or ASXL1 mutations can also occur after JAK2 during leukemic transformation.² Notably, transformed leukemic blasts in JAK2-mutated MPNs are frequently negative for the JAK2 mutation, suggesting these blasts may have evolved from a separate or coexisting clone with mutations in another gene, such as TET2.^22,23

Hydroxyurea is commonly used for cytoreduction in the management of MPNs. Hydroxyurea interferes with DNA synthesis and may exhibit mutagenic and leukemogenic potential. However, a recent study indicated that the use of hydroxyurea did not increase the risk of secondary malignancies, including AML and myelodysplastic syndrome.²⁴ Thus, it remains unclear whether hydroxyurea induces gene mutations that lead to leukemic transformation.

Table 1: Gene mutations frequently observed in secondary leukemia arising from myeloproliferative neoplasms.^1–5

Gene	Function	Frequency (%)	Occurrence	Clinical Impact
ASXL1	Chromatin remodeling	13–40	Most commonly prior to JAK2V617F	Adverse prognostic impact
IDH1/2	DNA methylation	12–21	Generally after JAK2V617F	Adverse prognostic impact
TP53	Transcription regulator	16–50	Generally after JAK2V617F	Adverse prognostic impact
NRAS/KRAS	Signal transduction	14	Generally after JAK2V617F	Adverse prognostic impact
TET2	DNA methylation	19–28	Most commonly prior to JAK2V617F	No prognostic impact reported
SRSF2	Splicing	7–22	Prior to JAK2V617F	Adverse prognostic impact
RUNX1	Transcription regulator	13–20	Most commonly prior to JAK2V617F	Adverse prognostic impact
DNMT3A	DNA methylation	3–17	Most commonly prior to JAK2V617F	No prognostic impact reported

Post-MPN AML with t(8;21)

Cytogenetic and gene mutational profiles in secondary AML arising from MPNs have been shown to differ distinctly from those of de novo disease. The high frequency of TP53 mutations and high-risk cytogenetic abnormalities suggests increased chromosomal instability.^1–5 By contrast, balanced chromosomal translocations, such as t(8;21), inv(16)/t(16;16), and t(15;17), which are frequently observed in de novo AML, are quite rare in post-MPN AML. These chromosomal aberrations result in the generation of transcription factor fusions that block hematopoietic cell differentiation.

Thirteen cases of acute promyelocytic leukemia with t(15;17); PML::RARA arising from MPNs have been reported.^10–18 Chromosomal rearrangements involving the core binding factor genes, t(8;21); RUNX1::RUNX1T1 or inv(16)(p13.1q22)/t(16;16); CBFB::MYH11, are extremely rare. As shown in Table 2, four cases of secondary AML with t(8;21) arising from MPNs (two PV and two ET) have been reported.^6–9 To the best of our knowledge, no cases of post-MPN AML with inv(16)/t(16;16) have been reported.

Among the four cases with t(8;21), JAK2V617F was identified by MPN disease driver mutation analysis in two cases (cases 3 and 4 in Table 2). One patient (case 3) had ET-derived AML as reported by us,⁸ and the other (case 4) had PV-derived AML, as reported by Tsukiji et al.⁹

Our patient (case 3)⁸ is a 74-year-old Japanese woman who was diagnosed with ET two years earlier and had been treated with hydroxyurea. She presented with leukocytosis and was diagnosed with ET-derived AML. She was treated with venetoclax and azacitidine, resulting in complete remission after one cycle. She developed sepsis and pneumonia during the second cycle, chose best supportive care, and survived for two years without apparent recurrence of AML.

The other patient (case 4)⁹ is an 87-year-old Japanese man who was diagnosed with PV 22 years earlier and had been treated with hydroxyurea. He presented with leukocytosis and was diagnosed with PV-derived AML. He was treated with venetoclax and azacitidine, but showed treatment resistance and died eight months after diagnosis of AML.

In both cases, JAK2V617F was present in leukemic-phase samples similar to the chronic phase, indicating leukemic evolution with the RUNX1::RUNX1T1 fusion gene from a JAK2-mutated MPN clone. Both cases presented typical morphological and immunophenotypic features associated with t(8;21) AML, including expression of CD19 and CD34. These findings indicate that a late-appearing cytogenetic abnormality can also define the phenotype of secondary AML. Mutations in FLT3 were not detected in either patient. A limitation of these studies is the lack of next-generation sequencing data for mutations commonly associated with MPN transformation, such as TP53, ASXL1, IDH1/2, TET2, and SRSF2. Both patients were treated with venetoclax and azacitidine, resulting in complete remission in one patient (case 3)⁸ and refractory disease in the other (case 4).⁹

Table 2: Reported cases of secondary AML with t(8;21) arising from MPN.

Case	Before Transformation					After Transformation
	Diagnosis	Age (yr)/Gender	Duration MPN→AML (yr)	Mutation (Chronic Phase)	MPN Treatment	Karyotype	Mutation Status (AML Phase)	Blast Immunophenotype	AML Treatment	Clinical Outcome
1	ET	73/F	1.4	NA	Busulphan	46,XX, t(8;21)(q22;q22)	RUNX1-rearranged	NA	No treatment	Died with sepsis
2	PMF/PV	51/F	13	NA	Hydroxyurea, ³²P	46,XX, t(8;21)(q22;q22), +18, +der(21)t(8;21)	RUNX1::RUNX1T1	NA	Cytarabine + 6-MP; intrathecal	Died with cerebral hemorrhage
3	ET	74/F	2	JAK2V617F	Hydroxyurea	46,XY, t(8;21)(q22;q22.1)	JAK2V617F RUNX1::RUNX1T1	CD13+ CD19+ CD34+	VEN/AZA → CR; BSC after infection	Survived >2 years
4	PV	87/M	22	JAK2V617F	Hydroxyurea	46,XY, t(8;21)(q22;q22.1)	JAK2V617F RUNX1::RUNX1T1	CD13+ CD19+ CD34+	VEN/AZA (refractory)	Died with refractory disease

Biological and Clinical Significance of the Coexistence of t(8;21) and JAK2 Mutation

The coexistence of JAK2V617F mutation and t(8;21) chromosomal translocation is a rare, but recurrent combination of genetic aberrations in AML. JAK2 mutations have been reported to occur in a small number of de novo AML cases, with a relatively high incidence in t(8;21) AML.^25–27 Additionally, JAK2 has been postulated to act as a cooperative mutation in therapy-related t(8;21) AML.²⁸ It remains undetermined whether de novo t(8;21) AML with JAK2 mutation and JAK2-mutated MPN with t(8;21) share the same biological entity.

According to the two-hit model,²⁹ leukemogenesis in AML requires cooperation of at least two different types of mutations: class I mutations induce proliferation of myeloid cells by activating signal transduction pathways, whereas class II mutations are frequently represented by balanced chromosomal translocations and gene fusions, such as t(8;21); RUNX1::RUNX1T1, inv(16)/t(16;16); CBFB::MYH11, or t(15;17); PML::RARA. These translocations affect genes encoding DNA-binding proteins or cofactors that play important roles in the differentiation of hematopoietic cells, and the formation of fusion products has been shown to interfere with transcriptional activity, leading to disruption of cell maturation.

The JAK2 mutation mediates increased activity of the JAK/STAT pathway, and increased cell proliferation and survival are considered characteristic of a class I mutation in accordance with this model. The RUNX1::RUNX1T1 chimeric gene product, which is assumed to repress myeloid-specific promoters and suppress the transcriptional activity of normal RUNX1, represents a class II mutation in this context.²⁹

t(8;21) AML is one of the most common subtypes of AML with recurrent genetic abnormalities and is associated with a favorable therapy outcome. RUNX1::RUNX1T1 is not thought to be sufficient to initiate leukemia and secondary events are needed.³⁰ Among cooperating mutations, the JAK2 mutation, as well as FLT3 and KIT, was shown to be an unfavorable prognostic factor in t(8;21) AML.^25–27 These mutations directly affect cytokine receptors or associated molecules, and may have more potent effects on leukemic transformation in t(8;21)-bearing cells than other types of mutations in signal transduction systems such as RAS family genes.

In de novo AML, JAK2 mutation is recognized as an additional genetic event occurring after the formation of the RUNX1::RUNX1T1 chimeric gene. In cases of post-MPN AML, the opposite order of events—JAK2 mutation preceding the acquisition of t(8;21)—has been postulated, indicating that the occurrence of t(8;21) can represent a late event in the progression of MPNs, similar to reported cases of chronic myeloid leukemia (CML) with concurrent t(8;21) translocation and the Ph chromosome.^31–33 In this situation, the acquisition of t(8;21), as well as inv(16), was reported to be associated with poor prognosis in CML.³³

The impact of t(8;21) or t(15;17) on leukemogenesis and prognosis in post-MPN AML remains undetermined. These translocations directly affect specific transcription factors involved in myeloid differentiation. However, it may be postulated that in most cases without these translocations, impairment of hematopoietic cell maturation is induced by multiple mechanisms driven by genomic instability and mutational complexity, resulting in resistance to standard chemotherapy for AML. Secondary AML with t(8;21) or t(15;17) might therefore exhibit different therapeutic responses due to distinct leukemogenic mechanisms compared with most other cases.

The significance of t(8;21) in secondary AML evolving from JAK2-mutated MPNs also remains undetermined, as one patient showed a good response whereas the other was refractory to venetoclax plus azacitidine therapy.

Post-MPN AML is a subset of myeloid malignancy with extremely poor prognosis. However, additional genetic aberrations beyond disease driver mutations are diverse and some can be therapeutic targets.³ Indeed, cases of secondary acute promyelocytic leukemia with t(15;17) arising from MPNs have been reported to respond well to all-trans retinoic acid therapy.^9–17 Recent trials of IDH inhibitors have shown promising outcomes for IDH1/2-mutated cases,^3,34 which represent approximately 19% of post-MPN AML.

RUNX1::RUNX1T1-targeted therapy is also under investigation, and a promising result was reported in which a small molecule blocking the activity of the abnormal RUNX1::RUNX1T1 protein demonstrated high antitumor activity in a leukemia cell line with t(8;21).^30,35 In the future, application of molecularly targeted therapy may improve the treatment outcome of t(8;21) leukemia, including secondary AML arising from MPNs.

Conclusion

t(8;21); RUNX1::RUNX1T1, one of the most common cytogenetic aberrations in de novo AML, is rare in secondary AML arising from MPNs. It has been speculated that this rare subtype of post-MPN AML may develop through a distinct leukemogenic pathway and exhibit different clinical features from those of more typical cases characterized by mutations in epigenetic modifiers or spliceosome genes. However, clinical experience and observational data regarding this entity remain limited. The accumulation of such cases, as well as investigations on the synergistic effects of JAK2 mutation and the abnormal RUNX1::RUNX1T1 protein, will be useful for understanding the mechanisms of leukemic transformation in MPNs. Additionally, it is important for clinicians to evaluate additional mutations in post-MPN AML, as some of them can be therapeutic targets.

Conflict of Interest

The author declares no conflicts of interest associated with this manuscript.

Data Availability Statement

Data supporting the findings of this study are not publicly available because they contain information that compromises the privacy of the research participants. The data are available from the corresponding author (Yuichi Nakamura) upon reasonable request.

Acknowledgments

The author thanks Editage for English language editing.

Funding

This study was not supported by any external funding.

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