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(Paper co-edited with the European LeukemiaNet)
A case of sole i(4)(p10) in myelodysplastic syndrome
Written2013-07François Desangles, Aurélie Servonnet, Hubert Nielly, Serge Cremades, Jean-Etienne Pilo
Laboratoire de Biologie Medicale, HIA Val de Grace, 74bd Port-Royal, F 75005 Paris, France (FD, AS); Medecine - Oncologie, HIA Begin, 69 ave de Paris, F 94160 Saint Mande, France (HN, SC); Laboratoire de Biologie Medicale, HIA Begin, 69 ave de Paris, F 94160 Saint Mande, France (JEP)
Age and sex : 79 year(s) old male patient.
Previous History : no preleukemia
The patient had an acute myeloid leukemia (AML) of unknown type, 20 years ago
no inborn condition of note
Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement
WBC : 2.7 x 109/L ; Hb : 9.7 g/dL ; platelets : 73 x 109/L;
Bone marrow : hypercellullar, multilineage dysplasia: 13% blasts, no Auer rods, 12% ring sideroblasts, 4% basophils
Cyto pathology classification
Cytology : Refractory anemia with excess blasts (RAEB)
Precise diagnosis : RAEB2 (WHO 2008)
Date of diagnosis: 01-2013
Treatment : Azacytidine. Blood transfusions were no more needed since.
Complete remission : None
Treatment related death : -
Relapse : -
Status : Alive
Survival : 4 month(s)
Sample : Bone marrow ; culture time : 24 h ; banding : BHG
Results : 47,XY,+i(4)(p10).ish i(4)(p10)(FRGFR3++, wcp4+)[12] / 47,XY,+8[1]
Other molecular cytogenetics technics : FISH. probe cytocell: FGFR3/IGH; ERG1; RELN/TES; ETO/AML1 (RUNX1T1/RUNX1). probe Q-Biogene: wcp4.
Other molecular cytogenetics results : nuc ish 5p15(D5S721,D5S23x2)5q31(ERG1x2)[100] ; nuc ish 7q22(RELNx2)7q31(TESx2)[100] ; nuc ish 8q22(RUNX1T1x2),21q22(RUNX1x2)[100] ; nuc ish 4p16(FGFR3x4),14q32(IGHx2)[40/50] ; ish +i(4)4p16(wcp4+,FGFR3++)[3/3]
Figure 1: RHG; partial panel of chromosomes 4 and i(4)(p10).
Figure 2: one metaphase labelled by wcp4: two normal chromosomes 4 and one extra derived chromosome 4.
Figure 3: nuc ish(FGFR3x4,IGHx2); FGFR3 red and IGH green.
Figure 4: two normal chromosomes 4 labelled by an FGFR3 red probe, one extra chromosome labelled by an FGFR3 red probes and two normal chromosomes 14 labelled by an IGH green probe.
We present a new case of isochromosome 4p in a myeloid proliferation. The patient, a 79 years old man developed an MDS (RAEB2), occurring 20 years after an acute myeloid leukemia not otherwise documented. Cytogenetics on bone marrow aspirate revealed a unique abnormality in the karyotype, an additional isochromosome 4p. FISH with wpc4 and FGFR3 probes confirmed the i(4p) as an extra chromosome. The most frequent molecular/cytogenetic abnormalities in myeloid proliferations were absent: 5q31, 7q22-q31 probes (for del 5q or del 7q) and ETO + AML1 probes (for +8 or +21) showed no abnormality.
To our knowledge, this is the sixth reported case of myeloid proliferation with an isochromosome 4p as the sole karyotype abnormality. The previous published cases were M4-AML (3 cases), M2-AML (1 case) and RAEB-T (1 case) (Hagemeijer et al., 1981; Hoo et al., 1995; Chen et al., 1999; Soriani et al., 2010). In this short series, only one relapse is recorded after 9 months, it is the unique case of double i(4p); two cases are noted as being in complete remission and two are not documented. The present case is not relevant to the prognosis value of this karyotype anomaly: first, to date the duration of treatment is only three months, but also the age of the patient, and a previous history of AML are factors which impact the prognosis too greatly by themselves. Isochromosome 4p currently does not have a specific prognostic value in myeloid proliferations.
At the present time, what interpretation of i(4)(p10) can be proposed? "Considering that trisomy 4 as the sole abnormality of karyotype is common anomalies in AML and MDS", Chen et al. (1999) suppose that "amplification of genes on 4p but not on 4q may play a crucial role in the pathogenesis of MDS and AML". Recently, two genes located on chromosome 4 were identified as playing a role in myeloid proliferations. In 2003, Dvorak et al. have described the increased expression of FGFR3 (4p16), a member of the family of tyrosine kinase genes, in myeloid proliferating cells of CML and AML. Furthermore TET2 in 4q24 is a putative tumor suppressor in myeloid proliferations (Delhommeau et al., 2009; Jankowska et al., 2009, Vainchenker et al., 2011). Thus it can be assumed that the presence of a supernumerary isochromosome 4p can increase the expression of FGFR3 in 4p16 without increasing the copy number of the tumor suppressor gene TET2 in 4q24.
Call for collaboration
Internal links
Atlas Cardi(4p)
Cytogenetic follow-up of patients with nonlymphocytic leukemia. II. Acute nonlymphocytic leukemia.
Hagemeijer A, Hahlen K, Abels J.
Cancer Genet Cytogenet. 1981 Mar;3(2):109-24.
PMID 6944153
Supernumerary isochromosome 4p in ANLL-M4 myelomonocytic type is associated with favorable prognosis.
Hoo JJ, Gregory SA, Jones B, Szego K.
Cancer Genet Cytogenet. 1995 Feb;79(2):127-9.
PMID 7889503
A group of previously not recognized cytogenetic abnormalities in myeloid hematological malignancies.
Chen Z, Richkind K, Roherty S, Velasco J, Lytle C, Brothman AR, Sandberg AA.
Cancer Genet Cytogenet. 1999 Sep;113(2):162-5.
PMID 10484984
Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia.
Dvorak P, Dvorakova D, Doubek M, Faitova J, Pacholikova J, Hampl A, Mayer J.
Leukemia. 2003 Dec;17(12):2418-25.
PMID 14562121
Mutation in TET2 in myeloid cancers.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA.
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PMID 19474426
Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms.
Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, O'Keefe CL, Ganetzky R, McDevitt MA, Maciejewski JP.
Blood. 2009 Jun 18;113(25):6403-10. doi: 10.1182/blood-2009-02-205690. Epub 2009 Apr 16.
PMID 19372255
Double supernumerary isochromosome 4p in acute myelomonocytic leukemia.
Soriani S, Marbello L, Colosimo A, Scarpati B, Grillo G, Cesana C.
Leuk Res. 2010 Dec;34(12):e342-4. doi: 10.1016/j.leukres.2010.08.019. Epub 2010 Sep 21.
PMID 20863564
New mutations and pathogenesis of myeloproliferative neoplasms.
Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA.
Blood. 2011 Aug 18;118(7):1723-35. doi: 10.1182/blood-2011-02-292102. Epub 2011 Jun 7. (REVIEW)
PMID 21653328


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