i(4p) in myeloid malignancies

2016-06-01   Steven Richebourg 

1.Laboratoire de cytogénétique onco-hématologique, Département de Pathologie, Hôpital du Saint Sacrement, 1050 Chemin Sainte Foy, CHU de Québec - Université Laval, Québec; Département de médecine moléculaire, Faculté de Médecine, Université Laval

Abstract

Review on i(4p) in myeloid malignancies, with data on clinics, and the genes involved.

Clinics and Pathology

Disease

Acute Myeloid Leukemia, Myelodysplastic syndrome

Phenotype stem cell origin

7 cases are available. The WHO/FAB classification was: RAEB-T/RAEB-2 : 2 cases, M4-AML : 3 cases, M2-AML : 1 case, NOS-AML : 1 case

 

Date

age

sex

FAB

CR

Follow-up

Case 1

1981

63

M

AML4

yes

6 months

Case 2

1995

46

M

AML4

yes

12 months

Case 3

1997

32

M

AML2

-

-

Case 4

1997

60

F

RAEB-T

-

-

Case 5

2010

43

M

AML4

yes

12 months

Case 6

2013

79

M

RAEB2

no

4 months

Case 7

2015

65

M

AML

yes

7 months


Table 1: Cases of i(4)(p10) reported in myeloid neoplasms (M : male; F : Female; CR : complete remission)

Epidemiology

+i(4p) as sole cytogenetic aberration represents less than 1% of cases of myeloid malignancies. The median age is 60 years old (32-79), the M/F sex ratio is 6:1

Clinics

Supernumerary i(4p) cases can be divided into 2 distinct subgroups based on the presentation : AML and MDS. AML cases fit into the FAB classification of M2 or M4 AML, except for one case with no bone marrow evaluation. The 2 MDS cases fit into the 2008 WHO classification of RAEB-2 (Swerdlow et al., 2008).

Cytology

No particular cytologic feature is associated with the presence of a supernumerary i(4p). The median white blood cell count is 6.95 (2.7-49). Thrombocytopenia is reported in 5 of the 7 cases. Among AML cases, it seems there is an association with a monocytic differentiation: indeed three of the four precedent AML cases were classified into acute myelomonocytic leukemia (Hagemeijer et al., 1981; Hoo et al., 1995; Soriani et al., 2010) and in one case, despite the absence bone marrow evaluation and the absence of peripheral monocytosis, the expression of CD4 and CD11c on blast cells demonstrated by flow cytometry was consistent with this observation (Richebourg et al., 2016). No specific morphologic feature is described in MDS cases.
Cytometry No common phenotype arises from the 3 cases with phenotypic data published.

Genes

The 2 AML cases with molecular characterization demonstrate the same profile with the presence of NPM1 mutation and the absence of FLT3-ITD mutation (NPM1+/FLT3-ITD-).

Treatment

Therapeutic data are available for 3 of the 5 AML cases: the patients received idarubicine + cytarabine based induction chemotherapy followed either by no consolidation or consolidation by chemotherapy or autologous peripheral blood stem cell transplantation.
Therapeutic data are available for one of the two MDS cases: the patient received azacytidine and achieved transfusion independence.

Prognosis

100% of AML patients with follow up data achieved a complete remission. Only 1 case of relapse is reported, 1 year after the diagnosis. Interestingly, this case presented a double supernumerary i(4p) at diagnosis, which could be considered as a clonal evolution and may have had an impact on the risk of relapse.
Since no specific prognostic significance is attached to the presence of supernumerary i(4p), this abnormality should be included into the intermediate cytogenetic subgroups according to the ELN (Döhner et al., 2010) and R-IPSS (Greenberg et al., 2012) classifications for AML and MDS respectively.

Genes Involved and Proteins

Note
No specific gene or protein are described. Supernumerary i(4p) is reported as the sole karyotypic abnormality, both at diagnosis and relapse, suggesting its role as a primary genetic alteration in pathogenesis. The presence of extra isochromosomes leads to gain of genetic material and consequently to amplification of genes possibly involved in the neoplastic process. Overexpression of genes located on 4p but not on 4q may play a crucial role in the pathogenesis of MDS and AML with supernumerary i(4p). Different cancer associated genes mapping on the short arm of chromosome 4 such as CD38, FGFR3, MED28, S100P, RHOH or TACC3 may be involved. Among them, the role of FGFR3 in signal transduction and activation of multiple signaling pathways regulating cell proliferation, differentiation, migration and apoptosis is well known, and an oncogenic role for FGFR3 overexpression has already been proposed in various haematological disorders, including myeloid neoplasm (Dvorak et al., 2003). However, it remains speculative whether this a "dosage effect" of FGFR3 could account in the development of myeloid neoplasm with supernumerary i(4p).

Bibliography

Pubmed IDLast YearTitleAuthors
104849841999A group of previously not recognized cytogenetic abnormalities in myeloid hematological malignancies.Chen Z et al
198804972010Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet.Döhner H et al
145621212003Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia.Dvorak P et al
227404532012Revised international prognostic scoring system for myelodysplastic syndromes.Greenberg PL et al
69441531981Cytogenetic follow-up of patients with nonlymphocytic leukemia. II. Acute nonlymphocytic leukemia.Hagemeijer A et al
78895031995Supernumerary isochromosome 4p in ANLL-M4 myelomonocytic type is associated with favorable prognosis.Hoo JJ et al
208635642010Double supernumerary isochromosome 4p in acute myelomonocytic leukemia.Soriani S et al

Summary

Note

Isochromosome 4p10 results in the loss of the long arm (4q) and duplication of the short arm (4p) of one chromosome 4 leading to partial 4q monosomy and partial 4p trisomy.
This rare abnormality has been reported in different phenotypes of solid tumors (adenocarcinoma, squamous cell carcinoma, melanoma, leiomyosarcoma, astrocytoma, medulloblastoma), usually in complex karyotype, and in various types of haematological disorders: Acute Myeloid Leukaemia (AML), Myelodysplastic Syndromes (MDS), Hodgkin and non Hodgkin lymphoma, myeloma.
Whereas in solid tumors or lymphoid neoplasia this abnormality is observed as a part of complex karyotypes, in myeloid malignancies it is only reported as an isolated supernumerary i(4p), except for one case with a double supernumerary i(4)p (Soriani et al., 2010), assuming the fact that the gain of isochromosome 4p may be a sufficient event for the pathogenesis of myeloid neoplasia. To date, only 7 cases have been documented in myeloid neoplasms, all reported either in AML or MDS (Hagemeijer et al., 1981; Hoo et al., 1995; Chen et al., 1999; Soriani et al., 2010; Desangles et al., 2014; Richebourg et al., 2016).
According to literature, there is a male predominance since 6 of the 7 cases are male patients and, among AML cases, it seems there is an association with a monocytic differentiation of blast cells.
Because of its rarity, no specific prognosis significance is associated with the presence of a supernumerary isochromosome 4p in myeloid malignancies.
Atlas Image
+i(4p) G- banding - Courtesy Steven Richebourg

Citation

Steven Richebourg

i(4p) in myeloid malignancies

Atlas Genet Cytogenet Oncol Haematol. 2016-06-01

Online version: http://atlasgeneticsoncology.org/haematological/1634/i(4p)-in-myeloid-malignancies

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