TP53 in Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDSs) are heterogeneous for their morphology, clinical characteristics, survival of patients, and evolution to acute myeloid leukemia. Different prognostic scoring systems including the International Prognostic Scoring System (IPSS), the Revised IPSS, the WHO Typed Prognostic Scoring System, and the Lower-Risk Prognostic Scoring System have been introduced for categorizing the highly variable clinical outcomes. However, not considered by current MDS prognosis classification systems, gene variants have been identified for their contribution to the clinical heterogeneity of the disease and their impact on the prognosis. Notably, TP53 mutation is independently associated with a higher risk category, resistance to conventional therapies, rapid transformation to leukemia, and a poor outcome. Herein, we discuss the features of monoallelic and biallelic TP53 mutations within MDS, their corresponding carcinogenic mechanisms, their predictive value in current standard treatments including hypomethylating agents, allogeneic hematopoietic stem cell transplantation, and lenalidomide, together with the latest progress in TP53-targeted therapy strategies, especially MDS clinical trial data.

Comparison of acute myeloid leukemia and myelodysplastic syndromes with TP53 aberrations

“…A consecutive phase 3 study in patients with TP53 mutant MDS failed to meet the primary endpoint of a significantly increased CR rate (Press Releases | Aprea Therapeutics). A comprehensive discussion of ongoing clinical trials in this particular patient cohort has recently been published [ 45 ].…”

Allogeneic haematopoietic stem cell transplantation with decitabine-containing preconditioning regimen in TP53-mutant myelodysplastic syndromes: A case study

“…TP53 is a key tumour suppressor gene involved in fundamental biological processes required for genomic stability and is recurrently mutated in a subgroup of MDSs and AML ( 8 ). It has been proven to be an adverse marker in the prognosis of AML and MDS patients and is associated with an increased proportion of blasts in the bone marrow, thrombocytopenia, complex karyotypes, and resistance to lenalidomide, hypomethylating agents, and allo-HSCT, all of which result in poor outcomes for MDS cases with TP53 mutations ( 2 ). Interestingly, recent clinical trials have demonstrated that patients with MDS harbouring TP53 mutations displayed favourable responses to treatment with Dec ( 16 , 27 ).…”

“…Complex karyotype; Monosomal karyotype: 45, XY, del(5q) (q15 q35), -6, der (18) (18pter->q21.1::? ::6q11->6qter) [4]/ 44,idem,-3,add(8)(p11.2)[14]/ 43, idem,-3, add(8)(p11.2)-17 [2]/ 46, XY, del(5q), (q15q35),+11,-18 [2]/ 49, XY,del(5)(q15q35),+8,+11,+22 [1] 5q del, trisomy 8 by FISH Complex karyotype: 41-45, XY, ?del(3)(p23),?Inv(3)(?P25?Q23),-5,?Dic(7;20)(p13;q11)[cp16]/42,XY,?Del(3)(q21),-5, -7,?Dic(7;20)(p13;q11),+8,+9,-16,?Del(17)(p11),-18,-19 [1]/45, XY,?Inv(3)(?P25?Q23),-5,?Del(7) (p21),?Dic(7;20)(p13;q11),+22,+r [1]/41,XY,-1?Del(3)(p23),-5,?Del(7)(p13),-10,-18,-20 [1]/46,XY [8] 5q del, 7q del,trisomy 8 by FISH…”

“…TP53, a tumour suppressor gene, plays a vital role in tumour inhibition through regulation of cellular senescence, apoptotic pathways, metabolism functions and DNA repair ( 1 ). TP53-mutant myelodysplastic syndrome (MDS) accounts for 5–10% of de novo MDS and 25–30% of therapy-related MDS, which is associated with worse outcomes ( 2 – 4 ). Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment for MDS ( 5 ).…”

“…Abnormal karyotype: 46, XY, del(5)(q22 q35)[18]/ 46,XY[3] 5q del by FISHPatientComplex karyotype; Monosomal karyotype: 44, X, -Y, -5, inv (8) (p11.2 q24.1), add (12) (p13) [16]/ 44, idem, del (7) (q21)[2]/ 45, idem, +8, inv (8) (p11.2q24.1)[3] 7q del, 20q del by FISH Patient 5Complex karyotype; Monosomal karyotype: 44, XY, -2, del(5)(q31q33), add(6)(q23), der(7) del(7)(q22q32) inv(7)(p13q22),+inv(11)(q13q25),-16, -17,20, +der(?)t(2;? )[10]/44,idem,+6,-add(6)(q23),-inv(11) (q13q25),+add(16)(p13.3)[4]/44, idem+6, add(6)(q23), -inv(11)(q13q25),+ 16,+ add(16)(p13.3), -19[1]/ 46, XY[8] 7q del, trisomy 8 by FISH Patient Complex karyotype: 47, XX, +8[4]/ 47, sl, del(5)(q31q33)[2]/ 48,sdl,+mar[2]/ 59<3n>,XXX,-2,-3,-5,+8,-9,-10,-11,-12,-14,-16, -17, add (6) (q23), -inv(11) (q13q25),+16,+ add(16) (p13.3), -19[1]/ 46, XY[8] 5q del, trisomy 8 by FISH Patient Complex karyotype: 46, XX, add (21) (q22) [11]/45-46, X, -X, add (21) (q22), +mar[cp2]/46, XX[2] Patient 8…”