Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia

The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.

TREATMENT OF NEWLY DIAGNOSED ACUTE PROMYELOCYTIC LEUKEMIA IN A PREGNANT WOMAN

Описан клинический случай впервые выявленного острого промиелоцитарного лейкоза у 36-летней беременной женщины при сроке 16-17 нед. До родов ей проведены 2 курса химиотерапии по схеме AIDA: индукция ремиссии даунорубицин из расчета 60 мг/м - 2, 4, 6, 8 дни, АТRA 45мг/м с 1 по 15 дни, дексаметазон 2,5 мг/м х 2 р в день с 1- по 15 дни. Ремиссия достигнута после 1-го курса индукционной терапии. После завершения 2-го курса ХТ в периоде полной ремиссии острого промиелоцитарного лейкоза на сроке беременности 25 недель проведено кесарево сечение в условиях городского родильного дома. Через 2 нед после родоразрешения в условиях гематологического отделения проведены еще два курса консолидации ремиссии. Далее пациентка переведена на поддерживающую терапию согласно протоколу AIDA: АТRA 45мг/м с 1 по 15 дни каждые 3 месяца, Метотрексат 15 мг/м/сут еженедельно, 6-Меркаптопурин 50 мг/м/сут. В контрольных анализах миелограммы констатируется полная ремиссия - 2.5% бластных клеток при нормальном соотношении всех ростков кроветворения. The case of de novo acute promyelocyte leukemia in a 36 year old pregnant woman (gestation age 16-17 weeks) is described. Two courses of “AIDA” chemotherapy were performed. Remission was achieved after the first induction chemotherapy. A month after the second consolidation chemotherapy at gestation age 25 weeks a living premature fetus was delivered by means of Cesarean delivery. After the delivery two more consolidation courses and supportive chemotherapy were performed. The woman now has been on remission.