Chronic eosinophilic leukemia with erythroblastic proliferation and the rare translocation t(8;9)(p22;p24) with<i>PCM1–JAK2</i>fusion gene: a distinct clinical, pathological and genetic entity with potential treatment target?

Prochorec‐Sobieszek, Monika; Nasiłowska-Adamska, Barbara; Borg, Katarzyna; Kopeć, Izabella; Kos-Zakrzewska, Kinga; Juszczyński, Przemysław; Warzocha, Krzysztof

doi:10.3109/10428194.2012.661856

Cited by 11 publications

(9 citation statements)

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“…To verify PCM1-JAK2 target gene expression ascertained in T-cells in another setting, bone marrow and peripheral blood from a previously reported t(8;9) patient with a myeloid neoplasm, chronic eosinophilic leukemia (CEL) [17], were also analyzed.…”

Section: Methodsmentioning

confidence: 99%

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

et al. 2013

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Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2–translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.

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Section: Methodsmentioning

confidence: 99%

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

et al. 2013

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“…To verify PCM1-JAK2 target gene expression ascertained in Tcells in another setting, bone marrow and peripheral blood from a previously reported t(8;9) patient with a myeloid neoplasm, chronic eosinophilic leukemia (CEL) [17], were also analyzed.…”

Section: Cells and Patientsmentioning

confidence: 99%

T(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 Via STAT5

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Scherr

et al. 2012

Blood

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1567 Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they are believed to promote JAK2-oligomerization and autonomous signalling although the underlying mechanisms remain unclear. Affected entities are candidates for therapy with JAK2 signalling inhibitors. Among 200 peripheral T-cell lymphomas surveyed, we identified only two with JAK2 amplification and none with JAK2 translocations, confirming their rarity in T-cell neoplasias. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in cell lines established at indolent and aggressive phases of a cutaneous T-cell lymphoma. To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 genes most upregulated in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive phase cells, was partially restored by PCM1-JAK2 knockdown. Activation of the tumor suppressor SOCS3 by PCM1-JAK2 may follow structural alteration of JAK2 affecting the ternary complex it forms with SOCS3 and receptor proteins. Treatment with JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive mimicked knockdown results, highlighting JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5 as reported for JAK2V617F or ETV6/TEL-JAK2, thus extending the paradigm of STAT5 activation by JAK2 alterations in hematopoietic malignancies. MAC-1/2A/2B are the first JAK2– translocation cell line models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements. Disclosures: No relevant conflicts of interest to declare.

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“…In our series, the most notable clinical and morphological features of patients with JAK2 fusion genes included a marked male predominance, lack of hypereosinophilia (≥1.5 × 10 9 /L) in the majority of patients, pathognomonic giant paratrabecular islets of predominantly immature proerythroblasts, 36,37,57 and primary BP or relatively rapid progression to secondary BP in a significant proportion of patients. Patients can achieve CHR and CCR on ruxolitinib but it had to be stopped in all but one patient within the first 3 years, most frequently because of resistance, relapse or progression.…”

Section: Discussionmentioning

confidence: 77%

“…With censoring for allo SCT, OS was not different for patients treated with or without ruxolitinib (Figure 2). An allo SCT was performed in 18/49 (37%) patients 8,31‐33,36‐38,42,46,49,50,52,56 . Two further patients underwent an autologous SCT (auto SCT) after intensive chemotherapy for ALL 33,56 .…”

Section: Resultsmentioning

confidence: 99%

“…We therefore sought to evaluate the clinical characteristics and response to various TKI in 18 patients with myeloid neoplasms and associated PCM1‐JAK2 , BCR‐JAK2 or ETV6‐ABL1 fusion genes. In an extended analysis, we integrated our data into the reports of 40 patients with JAK2 fusion genes ( PCM1‐JAK2 , n = 28) 8,9,12‐15,28‐40 or BCR‐JAK2 (n = 12) 41‐52 and 14 patients with TKI‐treated ETV6‐ABL1 positive chronic myeloid neoplasms 16‐27,53,54 . This analysis provides a comprehensive overview of responses to TKIs in patients with these rare fusions.…”

Section: Introductionmentioning

confidence: 99%

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Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

et al. 2020

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We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1‐JAK2, n = 8; BCR‐JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6‐ABL1, n = 9). On ruxolitinib (median 24 months, range 2‐36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4‐78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6‐ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3‐60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6‐ABL1 positive patients.

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Chronic eosinophilic leukemia with erythroblastic proliferation and the rare translocation t(8;9)(p22;p24) withPCM1–JAK2fusion gene: a distinct clinical, pathological and genetic entity with potential treatment target?

Cited by 11 publications

References 10 publications

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

T(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 Via STAT5

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

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