Acute myeloid leukemia with 3q26 abnormality: An editorial perspectiveK Ghosh
Stem Cell Laboratory, Surat Raktadan Kendra and Research Centre, Surat, Gujarat, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_255_17
Source of Support: None, Conflict of Interest: None
Acute myeloid leukemia (AML) is a difficult disease to treat. However, the advent of extensive immunophenotyping, cytogenetics, molecular genetics profiling combining with morphology, and past experiences with how the disease behaves therapeutically in adults, in pediatric age group, as AML secondary to chemoradiotherapy, AML arising out of myelodysplastic syndrome (MDS), and AML-like features as an accelerated or blastic phase of other myeloproliferative disorders allows one to classify the disorder as (i) curable with current chemotherapy therapy (ii) incurable with current chemotherapy but allogenic hemopoietic stem cell transplantation has good chance of curing them with acceptable toxicity and side effects (iii) allogenic stem cell transplant can cure with higher levels of morbidity and mortality (iv) various types of targeted therapy toward identified molecular targets of the disease (e.g. genetic, epigenetic, or at mRNA or protein level of the cell) alone or in combination with chemotherapy (v) monoclonal antibodies directed toward some of the expressed antigens on leukemic cells in various combinations (vi) none of the above therapy works, so we have to evolve experimental therapy based on the understanding of the molecular pathology of the condition. AML with pathology of 3q26 chromosomal abnormality is one such subset of AML which is difficult to treat because the remission is short lasting spanning only few months. In the current issue of the journal, three cases with this pathology have been reported. The authors could get only three such cases out of 115 analyzed with karyotype over 8-year period, giving a prevalence of 2.6% which agrees well with the current literature. Two of the patients had this abnormality in all the chromosome plates examined, and one of the patients showed this abnormality in only one of the cells.
In all the three patients, there was loss of chromosome 7 which is also well known with this type of cytogenetic pathology, and all the patients had resistant disease though none had diabetes insipidus. This was unusual but not unheard of as 66% of patients with this pathology show diabetes insipidus. The very fact that in one patient only one cell showed the cytogenetic changes of the disease proves that this change itself is not constitutional and cannot explain similar changes in adenohypophysis explaining diabetes insipidus.
However, this disease has been reported in mother and daughter from the same family. Moreover, this pathology has also been reported from across the world,,,, though from this country, this is an early report.
This cytogenetic pathology was initially detected way back in 1985 by French workers in chronic myeloid leukemia (CML) patients who were undergoing blastic transformation. Subsequently, for a few years, this abnormality continued to be detected in CML and other myeloproliferative disorders when the aggressive phase of the disease was unfolding. Subsequently, the patients with MDS and AML were also found to be associated with similar chromosomal abnormality and clinically these patients presented with relatively high platelet count (10%–15%), patients with 3q26 abnormality were found to have platelet counts above 500 × 109/L, and a large number of patients presented with associated diabetes insipidus presumably of central origin irrespective of whether autopsy studies showed infiltration by leukemic cells or not. Diabetes insipidus in this condition is correctable by exogenous vasopressin and often remits with clinical remission of the disease.,
This particular subset of AML was suspected to be a new entity  which has been included in 2008 WHO classification of AML; however, authorities feel that, whether MDS or AML, patients with this cytogenetic change behave uniformly poorly and should be put together as one type of disease with a spectrum of blast count and morphology.
Over the time, molecular pathology of the 3q26 translocation has been worked out. This pathology consists of t(3)(q21, q26), t(3,3)(q21, q26), Ins t3(q26), del 3q21-26. This pathology originates due to breakage of a proto-oncogene site ecotropic virus integration (EVI) in 3q26.
EVI is a protooncogene. In association with upstream MDS gene, it normally forms a MDS–EVI COM plex family. In this subset of AML, there is breakage in this area, several splice variants are produced, and EVI mRNA and EVI protein is increased in leukemic cells. Normally, this gene product has both transcription activation and transcription inhibition motif as well as epigenetic modification capacity through histone acetylation and DNA methylation through its zinc finger domain, polyproline domain, and SET domain.
Some of these domains are disrupted with this pathology and they are capable of producing dysmegakaryopoiesis with micromegakaryocytes and myelodysplasia., However, though thrombopoietin gene is present in chromosome 3, thrombopoietin level in this condition is not increased and the cause of thrombocytosis is not known.
This translocation also disturbs the transcriptional activating area of GATA2 gene which has immense role in late hemopoietic cell differentiation. Hence, this pathology of 3q26 produces a type of haploinsufficiency of GATA2 transcription factor as a part of somatic mutation and produces a partial MonoMAC syndrome., However, why this AML is almost always associated with del 7 or del7q is an enigma. Del 7 is not essential for the production of diabetes insipidus, but it is possible that 3q26 cells get some growth advantage when associated with del 7/7q. Other chromosomal and genetic pathologies are often associated with this type of AML [Table 1].
Although diabetes insipidus in this disease remains an enigma, one of the theories of its occurrence is absorption of vasopressin by abnormal platelets and megakaryocytes., Presence of abnormally high serum levels of sodium (>150 mEq) along with immature immunophenotype with high proportion of CD34, CD117, human leukocyte antigen antigen DR related, and CD56 positive blast cells may alert the treating doctor of its presence, and dysmegakaryopoiesis with micromegakaryocytes will only strengthen the suspicion of 3q26 disease before karyotyping is done.
Treatment of this condition is difficult as remission is short lasting. However, studies have shown that Ras and receptor tyrosine kinase activity are upregulated in this disease, and a right kind of inhibitor targeting this pathway may eventually be available. All-transretinoic acid was successfully used in the current report. Similarly, Brazilian authors have used a combination of decitabine and lenalidomide in these patients with some success. Till that time, these patients should be properly counseled and should be quickly prepared for allogenic stem cell transplantation within the short window of first remission if other conditions, i.e. finance, donor, and center permit.
The authors of the present article need to be congratulated for bringing to the notice of Indian hematologists this important cytogenetic subset of AML with a syndromic presentation.